SE455198B - TETRAZINE DERIVATIVES, PREPARATION AND PHARMACEUTICAL COMPOSITION THEREOF - Google Patents

Description

455 198 2 a straight or branched chain alkyl or alkenyl group containing up to 4 carbon atoms, which may bear a phenyl substituent, which is optionally substituted with halogen atoms, alkyl or alkoxy groups containing up to 4 carbon atoms or one nitro group, a cycloalkyl group having 3-8 carbon atoms or a phenyl ~ group, which is optionally substituted by halogen atoms; alkyl or alkoxy groups containing up to 4 carbon atoms or a nitro group, R 7 and R 8, which may be the same or different, each represents a hydrogen atom or a straight or branched chain alkyl or alkenyl group, which contains up to 4 carbon atoms and which may bear a phenyl substituent, which currently substituted by halogen atoms, alkyl or alkoxy groups containing up to 4 carbon atoms or a nitro group, or a cycloalkyl group having 3-8 carbon atoms or a phenyl group, which is optionally substituted with halogen atoms, alkyl- or alkoxy groups containing up to 4 carbon atoms or one nitro group, or the group -NR 7 R 8 represents a piperidino- group, which is optionally substituted by one or two methyl groups, or a morpholino, pyrrolidin-1-yl, perhydroazepin-1- -yl-, piperazin-1-yl-, 4-methylpiperazin-1-yl- or 1,4-thiazine- -1-yl group, and Z 2 represents an oxygen or sulfur atom), A 2 represents a nitrogen atom or when Al represents a nitrogen atom A2 represents a nitrogen atom or a group -CR3 =, wherein R3 has the meaning given above, Z1 represents an oxygen or the sulfur atom and R 2 represent a group of the formula -S (O) n R 6, -so2NR7a8, -csNR7R8, -coNR7R9 or -CZZNHNOP were: n, few ", R 7, R 8 and Z 2 have the meaning given above and the group -NR 7 R 9 4 represents a heterocyclic group, or R 7 has the above meaning and R 9 represents a straight or branched chain alkyl or alkenyl group containing up to 4 carbon atoms, which has a phenyl substituent, which is optionally substituted with halogen atoms, alkyl or alkoxy groups containing up to 4 carbon atoms or a nitro group, or a phenyl group, which is optionally substituted with halogen atoms, alkyl- or alkoxy groups containing up to 4 carbon atoms or one nitro group, or when Al represents a hydrogen atom or a group -CR4 =, wherein R4 has the meaning given above and Z1 and A2 has the meaning given above, or when A1 represents a group -CH = and Z1 represent a sulfur atom and A2 has the above 10 15 20 25 30 35 40 3 455 198 R 2 represents a group of the formula -S (O) n R 6, -so2NR7R8, cz2NR7R8 enar czznnnoz, var: n, RÖ, R7, Rs and 22 does the above matter? and when R 2 and / or R 3 represent a sulfamoyl or monosubstituted sulfamoyl group and / or R 3 represents a carboxy group, salts thereof, especially alkali metal metal salts, for example sodium salts. Whenever the context so allows is meant in the present preparation by the compounds with the general formula shown in Fig. I to include said salts. The salts are especially useful as intermediates.

Cycloalkyl groups within the definition of the formula shown in Fig. I contains 3 to 8, preferably 6, carbon atoms.

The disclosures of British Patent Application No. 2104522 and equivalent patent applications in other countries which takes priority from the original UK patent application No. 8125791, for example, U.S. Patent Application No. 410656 compounds of the general formula shown in Figs. and, wherein R a straight or branched chain alkyl, alkenyl or alkynyl group containing up to 6 carbon atoms, each such alkyl, alkenyl or alkynyl group is unsubstituted or substituted with robbery one to three substituents selected from halogen atoms, straight or branched chain alkoxy, alkylthio, alkylsulfinyl and alkylsulfonyl groups containing up to 4 carbon atoms and even optionally substituted phenyl groups, and R 11 represents one carbamoyl group which may bear on the nitrogen atom or two groups per selected from straight and branched chain alkyl and alkenyl groups, each containing up to 4 carbon atoms, and cycloalkyl groups.

Said tetrazine derivative of the formula shown in Fig. II possess valuable antineoplastic activity, for example represents a hydrogen atom, a cycloalkyl group or against carcinoma, melanoma, sarcoma, lymphoma and leukemia, and they also possess valuable immunomodulatory activity and are useful in the treatment of organ and skin grafts and in treatment of immunological diseases.

The compounds of the formula shown in Fig. I of the present invention the present invention possesses similar properties with in some vision improvement. Q Said tetrazine derivative of the formula shown in fig. II is useful as intermediates in the manufacture of some of 10 15 20 25 35 40 455 198 the compounds of the formula shown in Fig. I according to the present invention invention, for example as described later in the present invention production. -.

Especially significant classes of associations with it formula shown in fig. I includes those which exhibit a or more of the following characteristics: (i) R 1 represents a methyl- or in particular a 2-halo- ethyl group, especially a 2-chloroethyl group; (ii) R 2 represents a group of the formula -SORÖ, -SOZRÖ, 7 8 6 -sozmz R. -coNR7R8 represents -coNHNoP especially those wherein R represents an alkyl, for example methyl group and those wherein R 7 represents a hydrogen atom or an alkyl, for example methyl- group and R 5 represents a hydrogen atom or an alkyl, e.g. methyl group or a benzyl group, optionally substituted with an alkoxy group, for example a 4-methoxybenzyl group; (iii) one of A1 and A2 represents a nitrogen atom and that others represent a group -CR3 =; (iv) R 3 represents a group R 4, wherein R 4 represents an alkyl, for example butyl, propyl, ethyl or especially methyl group; (v) A2 represents a nitrogen atom; (vi) Z1 represents an oxygen atom; and or (vii) Z 2 represents an oxygen atom.

Essential individual compounds with the general formula that shown in Fig. I includes the following: g 8- (§-benzyl-fl-phenylcarbamoyl) -3-methyl- [3§7-imidazoles, 1-d] - 1,2,3,3-tetrazin-4-one, A, 8- [§-benzyl-§- (4-methoxybenzyl) carbamoyl] -3- (2-chloroethyl) - [3 37- imidazo (3,1-d] -1,2,3,5-tetrazin-4-one, B, 8- (§-benzylcarbamoyl) -3- (2-chloroethyl) -3§] -imidazoZ3,1-d] - 1,2,3,5-tetrazin-4-one, C 3- (Z-chloroethyl) -8- [§- (4-methoxybenzyl) -E-phenylcarbamoyl] -EEQY-imi- dazoles, 1-dj-1,2,3, S-tetrazin-4-one, D, 3- (2-chloroethyl) -8- (§-phenylcarbamoyl) - [EEY-imidazoles, 1-d] -1,2,3, S- tetrazin-4-one, E, 8- (§-benzyl-§-phenylcarbamoyl) -3- (Z-chloroethyl) - [α-imidazo3,3-d] - 1, Z, 3,5-tetrazin-4-one, _ F, 3- (2-chloroethyl) -8- (§-methyl-§-phenylcarbamoyl) - [Bg] -imidazo [S, 1-d] - (IV 10 15 20 25 35 40 5 455 198 1,2,3,5-tetrazin-4-one, 8-Carbamoyl-3- (2-chloroethyl) -6-methyl- [3-imidazole] -1-d7-1,2,3,5- tetrazin-4-one, 3- (2-chloroethyl) -8- (§, §-dimethylsulfamoyl) - [BE] -imidazoles, 1-II- 1,2,3,5-tetrazin-4-one, 3- (2-chloroethyl) -8- (β-methylsulfamoyl) -α] -imidazo [3,1-q] - 1,2,3,5-tetrazin-4-one, 3- (2-chloroethyl) -8-methylsulfonyl- [3§] -imidazo- [S, 1-d7- 1,2,3,5-tetrazin-4-one, 3-methyl-8-methylsulfonyl- [3§] -imidazoles, 1-d] -1,2,3,5-tetrazine- -4-one, 3- (2-chloroethyl) -8- [§- (4-methoxybenzyl) sulfamoyl] - [3§] -imidazo- [Ε, 1-d] -1,2,3,5-tefrazin-4-one. 5- (2-cimeryl) -s-sulfamoyl-βg-imidazole, 1-dJ-1,2,2, s, s- tetrazin-4-one, 8-Carbamoyl-3- (2-chloroethyl) -LÉEJ-pyrazolo [3,1-d] -1,2,3,5- tetrazin-4-one, 8-carbamoyl-3-methyl- [3fi] -pyrazolo [E, 1-d] -1,2,3,5-tetra- zin-4-one, 3- (2-chloroethyl) -8-piperidinocarbonyl- [3,7-imidazo [3,1-d] 1,2,3,5-tetrazin-4-one, 6-butyl-8-carbamoyl-3- (2-chloroethyl) -α-fi] -imidazofa, 1-d] - 1,2,3,5-tetrazin-4 ~ 0n, 8-Carbamoyl-3- (2-chloroethyl) -6-cyclohexyl- [3,4-imidamyl] -1-d] 1,2,3,5-tetrazin-4-one, 8-Carbamoyl-3- (2-chloroethyl) -6-phenethyl- [3§] -imidazo [E, 1-d] - 1,2,3,5-tetrazin-4-one, " 6-Benzyl-8-carbamoyl ~ 3- (2-carbonethyl) - [3§] -imidazo [E, 1-d7 ~ 1,2,3,5-tetrazin-4-one, 8-carbamoyl-3- (Z-chloroethyl) -6-isopropyl ~ [ɧ] -imidazo [É, l-d] - 1,2,3,5-tetrazin-4-one, 8-Carbamoyl-3- (2-chloroethyl) -6-propyl- [3fi] -imidazo [3,1-d] - 1,2, 3,5-tetrazin-4-one, 8-Carbamoyl-3- (2-chloroethyl) -6-ethyl- [Bg] -imidazo [B, 1-d] - 1,2,3,5-tetrazin-4-one, ¿ 3- (2-chloroethyl) -8- (4-methoxybenzyl) sulfamoyl-6-methyl- [3§] - imidazo [S, 1-Q] -1,2, 3,5-tetrazin-4-one, 3- (2-chloroethyl) -6-methyl-8-sulfamoyl- [3§] -imdiazo [3,1-q7- 1,2,3,5-tetrazin-4-one, W 3- (Z-chloroethyl) -8-dimethylsulfamoyl-6-methyl [3 3] -imidazo [B, 1-Q] - 10 15 20 25 40 455 198 6 1,2,3,5-tetrazin-4-one, ß U I AA, 3- (2-chloroethyl) -6-methyl-8-methylsulfonyl [3 3] -imidazo [S, 1-d] - 1,2,3,5-tetrazin-4-one, BB, 3- (2-chloroethyl) -8- (dimethylcarbamoyl) - [3,7-pyrazolo [3,1-Q] - 1,2,3,5-tetrazin-4-one, CC, and s- (z-chloroethyl) -s- (g-nitrocarbamoyl-β ¿E, l-d] -1,2,3,5-tetrazin-4-one, DD, 3-methyl-8-methylsulfonyl-α, β-pyrazolo [3,1-q] -1,2,3,5- tetrazin-4-one, EE, 3- (Chloroethyl) -8-methylsulfonyl- [3§7-PYrazolo- [S, 1-d]] - 1,2,3,5-tetrazin-4-one, FF, 3- (2-Chloroethyl-6-methyl-8-methylsulfinyl] -imidazo [1,1-d] - 1,2,3,3-S-tetrazin-4-one, GG, 3- (2-chloroethyl) -8-ethylsulfonyl-6-methyl [Kg] -imidazole, 1-d] - 1,2,3,5-tetrazin-4-one, HH, and 3- (2-chloroethyl) -6-methyl-8-propylsulfonyl [3§] -imidazole, 1-d7 1,2,3,5-tetrazin-4-one. I1_ The letters A to II have been assigned to the associations for to facilitate the latter description.

Compounds of special importance include the compounds C, K, L, M, O, Q, R, W, X and DD, especially the compounds I, J, N and BB and in particular the compounds H, Z, AA and CC.

The new tetrazine derivatives of the general formula shown in Fig. I have been shown to be particularly active in mice on a daily basis doses of between 0.2 and 320 mg / kg animal body weight administered intraperitoneally to TLXS (S) lymphoma according to the procedure of Gescher et al., Biochem. Pharmacol. (1981), âg, 89, and ÅDJ / PC6A and M5076 (reticulum cell sarcoma). Gentemot leukemia L12l0, in ~ operated intraperitoneally, intracerebrally and intravenously and P388 according to the procedure described in the "Methods of ment of New Anticancer Drugs "(NCI Monograph 45, March 1977, pages 147-149, National Cancer Institute, Bethesda, USA), wherein the compounds were active both intraperitoneally and orally at doses of between 1 and 320 mg / kg animal body weight. Inhibition of both primary tumor and metastasis were obtained against Lewis lung lung carcinoma at similar doses. Against B16 melanoma and C38 tumor in mice (NCl Monograph 45, 9p¿ git¿) were the compounds active intraperitoneally at doses between 6.25 and 40 mg / kg animal body weight. Against colon carcinoma C26 in mice 10 15 20 30 35 40 7 455 198 subcutaneous inoperation, the compounds were orally active in doses of between 2 and 40 mg / kg animal body weight.

The compounds of the general formula shown in Fig. I can be produced by applying or adapting i and for known procedures.

According to one aspect of the present invention, there is provided the compounds of the general formula shown in Fig. I, wherein R 2 is other than sulfamoyl-, mono (phenyl optionally substituted) with halogen atoms, alkyl or alkoxy groups containing up to 4 carbon atoms or a nitro group) carbamoyl, mono (phenyl optionally substituted with halogen atoms, alkyl or alkoxy groups containing up to 4 carbon atoms or a nitro group) thiocarb moyl, nitrocarbamoyl or nitrothiocarbamoyl group, by reaction of a compound of the general formula shown in Fig. III in the drawing [wherein A1 and A2 have the meaning given above and R12 represents a group within the above definition of R2 otherwise than a sulfamoyl, mono (phenyl optionally substituted with halogenated atoms, alkyl or alkoxy groups containing up to 4 carbon atoms or a nitro group) carbamoyl, mono (phenyl optionally sub- substituted with halogen atoms, alkyl or alkoxy groups containing containing up to 4 carbon atoms or a nitro group) thiocarbamoyl-, nitrocarbamoyl or nitrothiocarbamoyl group] with a compound with the general formula: Rïnczï Iv wherein R 1 and Z 1 are as defined above. The reaction can be carried in the absence or presence of an anhydrous organic solvent, for example a chlorinated alkane, such as dichloro- methane, or ethyl acetate, acetonitrile, §-methylpyrrolidin-2-one or hexamethylphosphoramide, at a temperature of between 00 and 120 ° C. The reaction can be carried out for up to 30 days. Light should preferably be excluded from the reaction mixture.

According to a further aspect of the present invention there is provided compounds of the general formula shown in Fig. I, wherein R 2 represents a sulfamoyl-, monosubstituted sulfamoyl-, carbamoyl-, monosubstituted carbamoyl-, thiocarbamoyl- or monosubstituted thiocarbamoyl group, wherein R 1, A 1, A 2 and Z 1 has the above significance, of corresponding associations within the framework for the general formula shown in Fig. I, wherein R represent 1 7 13 .Z 12 13 u represents a group of the formula -SO7hR R or -CL NR R (dar 10 lS 20 25 40 455 198 8 R13 represents an optionally substituted benzyl group and ZZ and R7 have the meaning given above) by application or adaptation of known procedures per se of optionally substituted benzyl groups with hydrogen amotors.

Suitable reaction conditions include, for example, catalytic hydrogenation (using a catalyst such as palatine carbon on charcoal, and in a solvent such as ethyl acetate or dimethylformamide); or when R 13 represents a substituted benzyl group, in which the substituent or loses one of the substituents The agents supported by the benzyl group are an alkoxy group (e.g. pelvis methoxy) in the 2- or p-position, preferably by trifluoroacetic acid, preferably in the presence of ani- sun and usually at or near room temperature.

According to a further aspect of the present invention there is provided compounds of the general formula shown in Fig. I, wherein R 2 represents a group of the formula -C 2 ZNHNO 2 (wherein Z 2, A1, A2 and Z1 have the meaning given above) by nitration of compounds of the general formula shown in Fig. V of the drawing 14 represents a group of the formula -CZZNHZ ningen, where R (wherein Z 2, R 1, A 1, A 2 and Z 1 have the meaning given above). Reactive the reaction can be carried out at or below room temperature, preferably between 0 ° and 10 ° C, in the presence of a nitration mixture, such as a mixture of concentrated sulfuric acid and concentrated nitric acid tersyra.

According to a further aspect of the present invention there is provided compounds of the formula shown in Fig. I, wherein R A1, A2 and RZ 1 a sulfur atom, of compounds of the general formula shown in Fig.-VI in the drawing (wherein R1, A1 and A2 have the meaning) and R1s represents a group of the formula -SCO) R n -so2NR7R8, -cz2NR7R8 or -czznnnoz (wherein RÖ, R7, R8, fi'0 ch 2 has the meaning given above and Z represents 2 has the meaning given above) by the action of phosphorus pentasulfide.

The reaction can be carried out in an organic solvent, e.g. an aromatic solvent such as benzene, toluene or xylene, or in pyridine or a derivative such as lutidine, and preferably at elevated temperature, for example between S00 and 1 ° C.

According to a further aspect of the present invention there is provided compounds of formula I, wherein R 1, Al, A and Z have 10 15 20 25 35 40 9 455 198 above and R 2 represents a group of meln -CSNR7R8, of compounds of the formula shown in Fig. VII in the drawing, wherein R1, A1, A2 and R 16 represents a group of the formula -CONR 7 R 8 (wherein R 7 and Z1 has the meaning given above and R 8 are as defined above) by reaction with phosphorus pentasulfide under conditions similar to those previously described for the reaction of phosphorus pentasulfide with compounds of the formula shown in Fig. VI.

The above salts of certain compounds of the formula shown in Fig. I was prepared by application or adaptation by methods known per se, for example by turnover of the parent compound of the formula shown in Fig. I with an alkali metal hydroxide, carbonate or preferably -hydrocarbonate in an aqueous or water-organic medium followed by isolation of the salt by methods known per se.

When a mixture of products is obtained in any of the above mentioned procedures, they can be separated by application or adaptation of methods known per se, for example chromatography graph.

Compounds of the general formula shown in Fig. III can be produced by applying or adapting i and for known methods, for example methods described by Shealy gt al., J. Org. Chem. (1961), gg, 2396 and Cheng et al., J. Pharm. Sci. (1968), eel, l044 and methods as in the continuation described in the reference examples.

With the expression "methods known per se" as such used in the present preparation are referred to as processes which hitherto used or described in the literature.

The following examples illustrate the preparation of compounds of the general formula I according to the present invention and the reference examples illustrate the preparation of intermediates.

EÄÉMPEL l Association A Sodium nitrite (0.44 g) was dissolved in an aqueous solution of acetic acid (2M; 10 ml) at 0 ° C, and the solution was stirred at 0 ° C and treated with the finely ground 5-aminoimidazole-4-§-benzyl-§-phenyl- carboxamide hydrochloride (0.7 g; prepared as described in Ref. cleaning example 1) in small portions. After 10 minutes it was extracted 10 15 20 25 40 455 198 10 the gummy solid formed with ethyl acetate (2 x 20 ml).

The combined ethyl acetate extracts were washed with water and dried over magnesium sulfate.

The resulting solution of 5-diazoimidazole-4-§-benzyl-§- phenylcarboxamide was treated with methyl isocyanate (5 ml), and the mixture was stirred at room temperature in the dark for 24 hours.

The solution was then evaporated to a small volume and the residue subjected to column chromatography at medium pressure under eluent with ethyl acetate to give 8- (§-benzyl-§-phenylcar- bam @ y1) -3-methyl3g7-imiaazois, 1-47-1, z, s, s-ferrazin-4-one (o, zz g), in the form of a white, crystalline solid, m.p. 168-170 ° C (during decomposition). [Elemental analysis C, 62.6; H, 4.41; N, Z2.3%; Calculated: C 63.32; H 4.47; N 23.32%; I.R. (KBr disc): 3100, 1735, 1620 cm -1; NMR (in DMSO-d 6): singlets at 3.75, 5.10 and 8.55 ppm, multiplet at 7.0-7.4 ppm; m / e 360 (M + 1].

EXAMPLE Z Sodium nitrite (3.7 g) was dissolved in an aqueous solution of acetic acid (2M; 3Sml) at 0 ° C, and the solution was stirred at 0 ° C and treated with a solution of S-amino-imidazole-4-§-benzyl-§f (4-methoxybenzyl carboxamide hydrochloride (2.2 g; prepared according to reference Example 2) in 1,2-dimethoxyethane (10 ml) dropwise. A reddish gum was separated, which was extracted with ethyl acetate (2 x 20 ml).

The combined ethyl acetate extracts were washed with water and with saturated aqueous sodium chloride solution and dried over sodium chloride sulphate. " The resulting solution of 5-diazoimidazole-4-§-benzyl-§- (4- methoxybenzylcarboxamide was treated with 2-chloroethyl isocyanate (2 ml) and the mixture was allowed to stand at room temperature in the dark for 24 hours.

The solution was then evaporated to a small volume and the residue was column chromatography was discarded at medium pressure with elution with ethyl acetate to give crude 8- [E-benzyl] -§- (4-methoxy- benzyl) carbamoyl] -3- (2-chloroethyl) -Z- [f-imidazole [ε, 1-d] -1,2,3,5- tetrazin-4-one (1.5 g) as a brown oil.

EXAMPLE 3 The compound C 8- [E-Benzyl-fl- (4-methoxybenzyl) carbamoyl] -3- (2-chloroethyl) - n 10 15 20 25 30 35 40 455 198 [Eg] -imidazo [5,1-d] -1,2,3,5-tetrazin-4-one (1.5 g; raw material prepared as described in Example 2) and anisole (0.5 ml) was dissolved together in trifluoroacetic acid (Z0 ml) and allowed stand at room temperature for 18 hours. The mixture was evaporated then to dryness and the residue was subjected to column chromatography. graph at medium pressure during elution with a mixture (2: 1 v / v) of ethyl acetate and petroleum ether (b.p. 600-80 ° C) to form 8- (§-benzylcarbamoyl) -3- (2-chloroethyl) -β3] - imidazo [5,1-d] -1,2,3,5-tetrazin-4-one (0,4g) in the form of a colorless solid, m.p. 153-155 ° C (recrystallized from diethyl ether). Elemental analysis C 49.9; H 3.92; N 24.4; Cl 10.4%; calculated: C 50.53; H 3.94; N 25.26; Cl 1.065%; I.R. (KBr disc) 3370, 3150, 1755 and 1660 cm-1; NMR (in DMSO-d 6): singlets at 7.3 and 8.9 ppm, doublet at 4.4 ppm and triplets at 4.0, 4.6 and 9.05 ppmj. §G§gPEL 4 the association D Sodium nitrite (0.61 g) was dissolved in water (10 ml) and dissolved. The mixture was stirred at 0 ° C and treated with a crude solution 5-aminoimidazole-4 - fl- (4-methoxybenzyl) -§-phenylcarboxamide (2.5 g; prepared as described in Reference Example 3) in hydrochloric acid (2M; 9 ml) and 1,2-dimethoxyethane (15 ml) dropwise. After 20 minutes, the solution was extracted with ethyl acetate (3 x 50 ml), and the combined extracts were dried over magnesium sulphate and concentrated evaporated to give 5-diazoimidazole-4 - (4-methoxybenzyl) - -§-phenylcarboxamide (2.8 g) as an orange oil.

This oil was dissolved in ethyl acetate (40 ml) and treated with 2-chloroethyl isocyanate (8 ml). The mixture was allowed to stand in ker in S day. The solution was evaporated to small volume and it obtained residue was subjected to column chromatography under model high pressure eluting with ethyl acetate to give 3- (2- chloroethyl) -8-ÅE- (4-methoxybenzyl) -§-phenylcarbamoyl] -L3§7-imidazo- (5,1-d] -1,2,3,5-tetrazin-4-one (1.5 g) as a gas, m.p. 55 ° C [NMR (in SMSO-d 6): singlets at 3.6, 5.0 and 8.5 ppm, triplets concentrated at 5.9 and 4.5 ppm, multiplet at 6.6- 7, ppm; I.R. (vessel disc) 1740 and 1640 cm'É7. 10 15 20 25 35 40 455 198 12 EXAMPLE 5 Association E 3- (Z-chloroethyl) -8- [§- (4-methoxybenzyl) -§-phenylcarbamoyl] - [3§] -imidazo [ε, 1-d] -1,2,3,5-tetrazin-4-one (1.0 g; prepared as described in Example 4) and anisole (0.2 ml) was dissolved in together with trifluoroacetic acid (10 ml), and the solution was allowed to stand at room temperature for 18 hours. The mixture was then evaporated to dryness and the residue was triturated with diethyl ether to formation of 3- (2-chloroethyl) -8- (§-phenylcarbamoyl) - [3§] -imidazo- [S, 1-d] -1,2,3,3-tetrazin-4-one (0.43 g) as a light brown colored solid, m.p. 166 ° C (during decomposition) (after reconstitution crystallization from ethyl acetate) Elemental analysis: C 48.4; H 3.22; N 26.0%; Calculated: C 48.99; H 3.48; N 26.37%; I.R. (Kßr-skivalz 3390, 1735 and 1680 cm -1; NMR (in DMSO-d 6) 2 singlets at 8.9 and 10.3 ppnn doublet centered at 7.8 ppm, triplets centered at at 4.0 and 4.6 ppm, multiplet at 7.0-7.9 ppmf; EXAMPLE 6 The association F Sodium nitrite (2.8 g) was dissolved in an aqueous solution of acetic acid (2M; 84 ml) and the solution was stirred at 0 ° C and traded with finely ground 5-aminoimidazole-4-§-benzyl-§-phenyl- carboxamide hydrochloride (2.8 g; prepared as described in Ref. cleaning examples 1) in small portions. After 10 minutes it was extracted the gummy solid formed with ethyl acetate (3 x 30 ml), and the combined extracts were washed with water and then with a saturated aqueous solution of sodium chloride and then dried over magnesium sulfate.

The resulting solution of S-diazoimidazo1-4-§-benzyl-§- phenylcarboxamide was treated with 2-chlorotyl isocyanate (9 ml), and the mixture was allowed to stand in the dark at room temperature for 4 days.

The solution was then evaporated to a small volume and the residue subjected to column chromatography at medium pressure under eluent with ethyl acetate to give 8- (§-benzyl-§-phenylcarba- moyl] -3- (Z-chloroethyl) - [3§7-imidazo [3,1-d2-1,2, 3,5-tetrazin-4-one (1.0 g) in the form of a glass [flementar analysis C 59.3; H 4.57; N 19.9; Cl 8.52; Calculated: C 58.75; H 4.19; N 20.56; Cl 8.67%; I.R. (KBr disk): 1740 and 1640 cm -1; NMR (in DMS0-d6): singlet at 5.2, 7.1, 7.3 and 8.6 ppm, triplets centered at : s 10 15 ZO 25 35 40 13 455 198 4.0 and 4.6 ppm].

EXAMPLE 7 The association G A solution of sodium nitrite (11 g) in water (50 ml) was cooled at 0 ° C and treated with a solution of S-aminoimidazole-b-rrzejyl-γ- phenylcarboxamide hydrochloride (4.0 g; prepared as described in Reference Example 4) in an aqueous solution of acetic acid (2M; 40 ml) drop by drop. After 10 minutes, the resulting mixture was extracted. one with ethyl acetate (4 x 100 ml), and the combined extracts filtered and dried over magnesium sulfate.

The resulting solution of 5-diazoimidazole-4-§-methyl-§- phenylcarboxamide was treated with 2-chloroethyl isocyanate (11 ml), and the mixture was allowed to stand in the dark at room temperature overnight.

The solution was then evaporated to a small volume and the residue subjected to column chromatography at medium pressure under eluent with ethyl acetate to give a solid (5.75 g).

This solid was decomposed with diisopropyl ether and then with dichloromethane. The insoluble residue was recrystallized from a mixture of petroleum ether (b.p. 60 ° -80 ° C) and ethyl acetate and then from a mixture of ethyl acetate and diisopropyl ether to give 3- (2-chloroethyl) -8- (D-methyl-fl-phenylcarbamoyl) - [Bg] -imidazo- [5,1-dj-1,2,3,5-tetrazin-4-one (0.8 g) in the form of a colorless solid, m.p. 130-132q [Elemental analysis: C 50.4; H 3.91; N 24.9; Cl 10.6%; calculated: C 50.53; H 3.94; N 25.26; Cl 1.065%; I.R. (KBr disk): 1750 and 1640 cm -1; NMR (in DMS0-d6): singlets at 3.4, 7.2 and 8.65 ppm, triplets centered at 3.95 and 4.6 ppm).

EXAMPLE 8 The association H A stirred suspension of 5-diazo-2-methylimidazole-4-carboxylate amide (1.54g; prepared as described in Reference Example S) in ethyl acetate (45 ml) was treated with 2-chloroethyl isocyanate (6.33 g) and the mixture was stirred at ambient temperature for 5 days in darkness. The mixture was then diluted with diethyl ether, and the The solids were filtered off, washed with diethyl ether and dried in vacuo at ambient temperature to give 8-carbamoyl-3- (2-chloroethyl) -6-methyl-δ] -imidazole, 1-d] -1,2,3,5- 10 15 20 25 30 b! U1 40 455 198 fl tetrazin-4-one (Z, 00 g), m.p. 170 ° C (during decomposition). basic analysis C 37.0; H 3.49; N 32.8; Cl 13.3%; calculated:' c 37.44; H 3.54; N 32.75; c1 13, s2ï7.

EXAMPLE 9 Association I A solution of 5-diazoimidazole-4- (N, N-dimethylsulfonamide) (0.55 g; prepared as described in Reference Example 6) i dry ethyl acetate (40 ml) was treated with 2-chloroethyl isocyanate (3 ml), and the mixture was stirred in the dark for 48 hours. Among- The mixture was then evaporated in vacuo at below 40 ° C to about 15 ml volume and diluted with dry diethyl ether. It formed solid the substance was filtered off to give 3- (2-chloroethyl) -8- (N, N-di- methylsulfamoyl) - [3 fl] -imidazo [E, 1-d] -1,2,3,5-tetrazin-4-one (0.68 g) in the form of grayish needles, m.p. 155-165 ° C. [Elementary Analysis: C 30.4; H 3.35; N 26.8; Cl 11, 8%; calculated: C 31.3; H 3.62; N 27.4; Cl 11, 6%; I.R. 1755 cm -1; NMR (in DMSO-d 6): singlets at 2.80, 8.90 ppm, triplets at 3.99, 4.62 ppm).

EXAMPLE 10 The association J Suspension of 5-diazoimidazole-4- (N-methylsulfonamide) (0.7 g; prepared as described in Reference Example 7) in ethyl acetate (40 ml) was treated with 2-chloroethyl isocyanate (3 ml), and the mixture was stirred in a closed flask in the dark for 48 hours.

The mixture was then evaporated in vacuo at below 35 ° C to about half its volume and diluted with diethyl ether. The The solid formed was filtered off and washed with diethyl ether to give 3- (2-chloroethyl]-8- (N-methylsulfamoyl) - [3 zo [É, 1-d] -1,2,3,5-tetrazin-4-one (0.32 μl in the form of shiny light yellow-brown plates, m.p. 147-148 ° C [Elemental analysis: C 28.5; H 2í90; N 28.7%; calculated: C 28.7; H 3.08; N Z8.7%; I.R. 1745 1 H NMR (in DMSO-δ: δ mlett at 2.58 ppm, triplets at 3.98, 4.61 ppm, quartet at 7.94 ppm, singlet at 9.84 ppmj.

EXAMPLE ll The association K A solution of 5-diazo-4-methylsulfonylimidazole (0.65 g; 10 15 20 25 30 35 40 15 to 455 198 prepared as described in Reference Example 8) in dry ethyl acetate (50 ml) was treated with Z-chloroethyl isocyanate (3 ml), and mixed The mixture was stirred at room temperature in the dark for 48 hours. Among- the residue was then evaporated in vacuo and the oily residue decomposed with petroleum ether (b.p. 60-80 ° C). It formed the solid was filtered off and subjected to chromatography at medium pressure eluting with ethyl acetate, and the white the solid product was decomposed with petroleum ether and filtered off. to give 3- (2-chloroethyl) -8-methylsulfonyl- [3§] -imida- zoL3,1-d] -1,2,3,5-tetrazin-4-one (0.72 g), m.p. 154-175 ° C. [Ele- mentar analysis: C 30.3; H 2.85; N 25.0; Cl 11, 5%; calculated: C 30.28; H 2.90; N 25.22; Cl ll, S5å].

EXAMPLE 12 A solution of 5-diazo-4-methylsulfonylimidazole (0.65 g; prepared as described in Reference Example 8) in dry ethyl acetate (60 ml) was treated with methyl isocyanate (3.5 ml) and left was allowed to stand at room temperature in the dark for 3 days. One more quantity of methyl isocyanate (3.5 ml) was added, and the mixture was heated at 40 ° C for 2 days and then allowed to stand at room temperature for 3 days. The mixture was then evaporated in vacuo to a volume of between 10 and 15 ml and subjected to chromatography at medium pressure eluting with ethyl acetate to give 3-Methyl-8-methylsulfonyl- [3§] -imidazo [S, 1-di-1, Z, 3,5-tetrazine-4- (0.7 g) in the form of a white crystalline solid, m.p. l86 ° C (during decomposition). Elemental analysis: C 31.2; H 2.89; N 30.3%; Calculated: C 31.44; H 3.08; N 30, S6%].

EXAMPLE 13 Förcning§n_ fl A solution of 5-diazoimidazole-4-LN- (4-methoxybenzyl) sulfonic acid amide (0.3 g; prepared as described in Reference Example 9) in dry ethyl acetate (25 ml) was treated with 2-chloroethyl isocyanate (1.5 g), and the mixture was stirred at room temperature for 48 hours. mar. The resulting dark solution was filtered and evaporated The resulting brown solid was decomposed with to dryness. petroleum ether, was filtered off and subjected to chromatography at medium pressure eluting with ethyl acetate to give 10 15 20 25 40 455 198 16 a white solid decomposed with petroleum ether, filtered off and dried at 70 ° C / 10 mmHg for 1 hour to give 3- (2-chloroethyl) -8- [§- (4-methoxybenzyl) sulfamoyl] - [3§] -imidazo- [S, 1-47-1.2, s, s-tetrazin-4-one (0.2 g), m.p. 1ss-1s6 ° c (below decomposition) [l.R. 1745 cm-1; Elemental analysis: C 41.9; H 3.72; N 20.5%; Calculated: C 42.16; H 3.79; N 21.07%].

EXAMPLE 14 The association N 3- (2-chloroethyl) -8- [§- (4-methoxybenzyl) sulfamoyl7- [3§] -imida- zo [S, 1-d] -1,2,3,5-tetrazin-4-one (0.1 g; prepared as described in as in Example 13) was dissolved in trifluoroacetic acid (1.0 ml) and anisole (3 drops), and the solution was allowed to stand at room temperature for two hours. The mixture was then evaporated in vacuo and the residue was triturated with diethyl ether to give one yellow solid, which was subjected to medium chromatography pressure using a mixture of petroleum ether (kpt. 60-80 ° C) and ethyl acetate (lzl v / v) as eluent to formation of 3- (2-chloroethyl) -8-sulfamoyl- [Bg] -imidazo [S, 1-d7- 1,2,3,5-tetrain-4-one (50 mg) as a white solid, m.p. l83 ° C (with decomposition) [l.R. 1750 cm -1 singlets at 8.8, 7.8 ppm, triplets at 4.58, 3.95 ppmj.

EXAMPLE 15 The association O A stirred suspension of 3-diazopyrazole-4-carboxamide (5.9 g; prepared as described by Cheng et §l¿, §i§¿) in ethyl acetate (150 ml) was treated with 2-chloroethyl isocyanate (24 ml) and Stirred at ambient temperature for 7 days in the dark. The mixture diluted with diethyl ether and the solid formed by filtration and washed with diethyl ether to give a mixture in the form of a cream solid (8.36 g), m.p. 173-174 ° C (during division).

A solution of a sample of said mixture (1.0 g) in dimethyl sulfoxide (20 ml) was heated at 60 ° C overnight. Loose- The mixture was then evaporated to dryness (at below 60 ° C and at pressure down to 0.1 mmHg) and the residue was decomposed by one mixture of dichloromethane and diethyl ether. The solid formed was collected and dissolved in boiling acetonitrile (about SO ml).

; NMR (in DMSO-d 6): 10 15 25 30 40 11 455 198 The resulting solution was treated with deactivated silica gel (3 g containing 20% water) and the mixture was evaporated to dryness. The residue was transferred to a silica gel column and subjected to chromatography at medium pressure eluting with ethyl acetate and recrystallization of the product from acetonitrile to give formation of 8-carbamoyl-3- (2-chloroethyl) - [3§] -pyrazolol, 1-d] -1,2,3,5- tetrazin-4-one (0.25 g) as colorless needles, m.p. 203-204 ° C (during decomposition) [Elemental analysis: C 34.8; H 2.92; N 34.7; Cl 14.6%; Calculated: C 34.65; H 2.91; N 34.64; Cl 14.6l%].

EXAMPLE 16 The association P A stirred suspension of 3-diazopyrazole-4-carboxamide (1.6 g; prepared as described by Cheng gt al¿, gg. git¿) and dichloro- methane (49 ml) and Q-methylpyrrolid-2-one (2.5 ml) were treated with methyl isocyanate (6 ml) and stirred in the dark for 7 days. Among- The mixture was then diluted with diethyl ether, and the solid formed the substance was filtered off to form a mixture in the form of a cream solid (2.24 g), m.p. 179-181 ° C (during decomposition ning).

A solution of a sample of this solid (1.0 g) in di- methyl sulfoxide (10 ml) was treated with deactivated silica gel (8 g; containing 20% water), and the mixture was evaporated dryness (at 60 ° C / 0.1 mmHg). The residue was transferred to the top a column of silica gel and subjected to chromatography at medium pressure during elution with ethyl acetate. The product disintegrates was divided with a small amount of saturated aqueous sodium hydrogen solution. carbonate and filtered rapidly to give 8-carbamoyl-3- Methyl-α form of a colorless solid, m.p. 1 ° C (below ning). / jwwn (in nMso-dm sincletres at 3.95. 1.45. 7.55. 8.50 ppm; 1.11. (The cure disc: 3400, sieo, 1750 and 1680 evil / _ EXAMPLE 17 compound Q A solution of sodium nitrite (0.79 g) in water (6 ml) is was treated with a solution of crude 4-amino-S-piperadinocarbonyl imidazole hydrochloride (2.1 g; prepared as described in reference Cleansing Example 10) in an aqueous solution of acetic acid (1M; 17 ml) 10 15 20 25 '41 C) 35 40 455 198 w dropwise with stirring at 5-10 ° C for 5 minutes. Solution were extracted with ethyl acetate (4 x 45 ml) and combined the extracts were dried over magnesium sulfate and evaporated 30 ° C / 0.1 mmHg. The residue was dried in a desiccator over phosphorus pen oxide for 45 minutes to give 4-diazo-S-piperidinocarbonyl- imidazole (1.73 g) in the form of red crystals sufficiently pure for use in the next step.

A solution of crude 4-diazo-5-piperidinocarbonylimidazole (1.73 g; prepared as described above) in dry ethyl acetate (53 ml) was treated with 2-chloroethyl isocyanate (5.9 ml) and mixed with The mixture was stirred in the dark for 2 days. The solution was then evaporated at 30 ° C / 0.1 mmHg and the residue was twice subjected to matography at medium pressure on silica gel eluting with a mixture of ethyl acetate and acetonitrile (88: 12 v / v).

Appropriate fractions were combined and evaporated and the residue decomposed with petroleum ether (b.p. 40-60 ° C) to give of 3- (2-chloroethyl) -8-piperidinocarbonyl- [Za-imidazola, 1-d] - 1,2,3,5-tetrazin-4-one (1.46 g) in the form of a light purple crystals, m.p. 92 DEG-94 DEG C. [Elemental analysis: C 45.3; H 4.98; N 26.1%; calculated: C 46.4; H 4.87; N 27.1%; NMR (in DMS0-d6): singlet at 8.7 ppm, triplets at 4.6 and 4.0 ppm, multiplet at 3.2 ~ 3.4 and 1.5-1.8 ppm; l.R. (KBr disc): 1750, 1630 cm-äj.

EXAMPLE 18 Eïëææëaß.

A stirred solution of sodium nitrite (1.6 g) in water (5 ml) was cooled and kept at S-10 ° C and treated dropwise with a solution. preparation of S-amino-Z-butylimidazole-4-carboxamide hydrochloride (1.6l g; prepared as described in the West German patent specification no 2358509) in hydrochloric acid (1M; 17.7 ml) for 5 minutes to give of a yellow precipitate, which was filtered off and dried in a eX5 fl $ fl UN 'over phosphorus pentoxide to give 2-butyl-5-diazo- imidazole-4-carboxamide (0.47 g) as a yellow solid, m.p. 109-111 ° C (during decomposition) sufficiently clean for reversal in the next step.

A solution of crude 2-butyl-S-diazoimidazole-4-carboxamide (0.47 g; prepared as described above) in ethyl acetate (14 ml) was treated with 2-chloroethyl isocyanate (1.5 ml) and allowed to stand in 10 15 20 25 30 40 19 455 198 for 24 hours. The light yellow-brown solid formed is filtered off. and recrystallized from a mixture of ethyl acetate and acetonitrile to give 6-butyl-8-carbamoyl-3- (2-chloroethyl) - [3 §7-imidazo [3,1-d] -1,2,3,5-tetrazin-4-one (0.49 g) in the form of colorless crystals, m.p. 165-167 ° C (during decomposition).

[Elemental analysis: C 43.9; H 4.90; N 27.9; Cl 1Z, 0%; calculated: C 44.2; H 5.06; N 28.1; Cl 1.1, 9%].

EXAMPLE 19 The association S A stirred solution of sodium nitrite (0.44 g) in water (3.7 ml) was cooled and kept at 5-10 ° C and treated dropwise with a solution of 5-amino-Z-cyclohexylimidazole-4-carboxamide hydro- chloride (1.1 g; prepared as described in West German patents Document No. 2358509) in an aqueous solution of acetic acid (2M; 28 ml) for 5 minutes. The orange precipitate formed is filtered off. and dried in desiccator over phosphorus pentoxide for 1 hour to give crude 2-cyclohexyl-5-diazoimidazole-4-carboxamide (0.86 g) in the form of an orange solid sufficiently pure for use in the next step.

A solution of the crude 2-cyclohexyl-S-diazoimidazole-4-carboxylate boxamide (0.86 g; prepared as described above) in ethyl acetate (17 ml) was treated with 2-chloroethyl isocyanate (2.0 ml). let stand in the dark for 24 hours. The solid obtained was triturated and recrystallized from ethyl acetate to give of 8-carbamoyl-3- (2-chloroethyl) -6-cyclohexyl- [β] -imidazo [S, 1-d] - 1,2,3,5-tetrazin-4-one (0.23 g) as colorless crystals, m.p. 245-248 ° C (during decomposition). Elemental analysis C 47.6; H 5.16; N 25.6; Cl 10.8%; calculated: C 48.1; H 5.28; N 25.9; Cl l0.9 $].

EXAMPLE 20 The association T A stirred solution of sodium nitrite (0.58 g) in water (4.1 ml) was cooled and kept at 5-10 ° C and treated dropwise with a solution. preparation of S-amino-2-phenethylimidazole-4-carboxamide hydrochloride (1.8 g; prepared as described in Reference Example 11) in an aqueous solution acetic acid (ZM; 18 ml) for 5 minutes. The obtained the yellow precipitate was filtered off and dried over phosphorus pentoxide for 1 hour to give crude 5-diazo-2-phenethyl- 10 15 20 25 30 35 40 455 198 20 imidazole-4-carboxamide (2.0 g) as a yellow solid sufficiently clean for use in the next step.

A suspension of crude 5-diazo-2-phenethylimidazole-4-carboxamide (2.0 g; prepared as described above) in ethyl acetate (29 ml) was treated with Zechloroethyl isocyanate (3.4 ml) and stirred in darkness for 24 hours. The solid formed was filtered off and was recrystallized twice from ethyl acetate to give 8-Carbamoyl-3- (2-chloroethyl) -6-phenethyl- [1,1-imidazo [5,1-d] -1,2,3,3 5-tetrazin-4-one (0.4 g) as colorless crystals, m.p. 179-18l ° C (during decomposition). [Elemental analysis: C 51.8; H 4.19; N 24.2; Cl 10.2%; calculated: C 52.0; H 4.36; N 24.2; Cl l0.2å].

EXAMPLE 21 The association U A solution of 2-benzyl-5-diazoimidazole-4-carboxamide (2.4 g; prepared as described in Reference Example 12) in dry ethyl acetate (150 ml) was treated with 2-chloroethyl isocyanate (10 ml) and the reaction mixture was allowed to stand at room temperature in for 20 hours. The reaction mixture was then evaporated to dryness and the residue was decomposed with petroleum ether (b.p. 60-80 ° C; Z x 30 ml) to remove excess 2-chloro- ethyl isocyanate. The remaining residue was then decomposed with dichloromethane (2 x 50 ml) for extraction of the desired product from the insoluble 1,3-bis (2-chloroethyl) urea by-product. They came- the combined dichloromethane extracts were evaporated to dryness and was subjected to chromatography under medium pressure on silica gel eluting with ethyl acetate. Appropriate fractions combined was evaporated and recrystallized from ethyl acetate to formation of 6-benzyl-8-carbamoyl-3- (2-chloroethyl) - [3§] -imidazo- ¿B, 1-aj-1,2, s, s-cetrazin-4-one (0.7 g), m.p. 161-163 ° C (below decomposition). [Elemental analysis C 50.4; H 3.96; N 25.4; Cl 10.8%; calculated: C 50.53; H 3.94; N 25.26; Cl 10.66%; 1.R. 1140 cm “É].

EXAMPLE 22 Association V A solution of 5-diazo-2-isopropylimidazole-4-carboxamide (1.2 g; prepared as described in Reference Example 13) in dry 10 15 20 40 H 455 198 ethyl acetate (75 ml) was treated with 2-chloroethyl isocyanate (5 ml), and the mixture was allowed to stand in the dark at room temperature for 5 days.

The crystalline solid formed was filtered off and washed with petroleum ether (b.p. 60-80 ° C) to give 8-carbamoyl- -3- (2-chloroethyl) -6-isopropyl- [3§7-imidazo [5,1-d] -1,2,3,5-tetra- zin-4-one (0.2 g), m.p. 189-190 ° C (during decomposition). [Elemen- tar analysis: C 42.0; J 4.64; N Z9.5%; Calculated: C 42.19; H 4.60; N 29.54; 1.R. 1740 em '¥ 7.

EXAMPLE 23 The association W A solution of sodium nitrite (0.7 g) in water (6 ml) was added to a solution of 5-amino-2-propylimidazole-4-carboxamide (1.37 g; prepared as described in West German Patent Specification No. 2358509) in an aqueous solution of acetic acid (2M; 22 ml) at 0-SCC, dropwise for 5 minutes. The precipitate formed was filtered off and dried. was desiccated over phosphorus pentoxide to give 5-diazo- -2-propylimidazole-4-carboxamide (0.56 g) as a yellow solid substance sufficiently clean 'for use in the next step.

A solution of crude S-diazo-2-propylimidazole-4-carboxamide (0.56g; prepared as described above) in dry ethyl acetate (14 ml) was treated with 2-chloroethyl isocyanate (1.6 ml) and stirred was kept in the dark for 24 hours. The precipitate formed was filtered off and washed with ethyl acetate to give 8-carbamoyl-3- (2-chloroethyl) -6-propyl- [Kg] -imido: [5,1-Q] -1,2,3,5-tetrazine-4- on (0.48 g) in the form of a light yellow-brown solid, m.p. 145-148 ° C (during decomposition). [Blementar analysis C 41.1; H 4.4; M 28.5%; calculated: C 42.2; H 4.60; N 29.5%; NMR (in DMSO-d 6): singlet at 7.7 ppm; triplets at 4.6, 4.0, 3.2 and 1.0 ppm, multiplctt at 1.8 ppm; I.R. (KBr-skivali 1750, 1695 cm_ {7.

EXAMPLE 24 compound3n_§ A stirred solution of sodium nitrite (0.44 g) in water (3.8 ml) was added to a solution of 5-amino-Z-ethylimidazole-4-carboxamide (0.8O g; prepared as described in the West German patent specification 10 15 20 25 30 35 22 455 198 No. 2358509) in an aqueous solution of acetic acid (2M; 14 ml) at 0-3 ° C dropwise over S minutes. The precipitate formed is and dried in 6XSíCk8IOT over phosphorus pentoxide for 1 hour to form 5-diazo-2-ethylimidazole-4-carboxamide (0.62 g) in form of a solid yellow substance, m.p. l§9 ° C (during decomposition) clean enough for use in the next step.

A solution of crude 5-diazo-Z-ethylimidazole-4-carboxamide (0.62) g; prepared as described above) in dry ethyl acetate (22 ml) was treated with 2-chloroethyl isocyanate (2.4 ml) and stirred in darkness for 24 hours. The precipitate formed was filtered off and was washed with ethyl acetate to give 8-carbamoyl-3- (2-chloro- ethyl) -6-ethyl-10β-imidazo [1,1-d] -1,2,3,5-tetrazin-4-one (0.09 g) in the form of pale gray crystals, m.p. 172-174 ° C (with decomposition ning). Elemental analysis: C 39.7; H 3.98; N 31.0; Cl 31.1%; calculated: C 39.9; H 4.10; N 31.0; Cl l3, l].

EXAMPLE 25 Association Y Dry ethyl acetate (100 ml) was treated with 5-diazo-4- (4- methoxybenzyl) sulfamoyl-2-methylimidazole (2.45 g; as described in Reference Example 14) followed by 2-chloroethyl iso- cyanate (3 ml) and the reaction mixture was stirred in the dark at room temperature for S6 hours. The mixture was then treated with an additional quantity of 2-chloroethyl isocyanate (3 ml) and stirring in the dark at room temperature for an additional period of 24 hours. Reactive The mixture was then evaporated to dryness and the residue was treated. with petroleum ether (b.p. 60-80 ° C; 3 x 25 ml) for removal of excess 2-chloroethyl isocyanate. The remaining residue then decomposed with dichloromethane (Z X 50 ml) for extraction of insoluble product from insoluble 1,3-bis (2-chloroethyl) ureabipro- duct. The combined dichloromethane extracts were evaporated dryness and subjected to chromatography at medium pressure silica gel eluting with ethyl acetate to give 3- (2- chloroethyl) -8- (4-methoxybenzyl) sulfamoyl-6-methyl- [SQ] -imidazolb, 1- d] -1,2,3,3-tetrazin-4-one (1.5 g), m.p. 159-160 ° C (during decomposition division) [l.R. 1760 cm-if.

EXAMPLE 26 Compound Z ' A solution of 5- (2-chloroethyl) -8- (4-methoxybenzyl) sulfamoyl- 10 15 20 25 b: _; 35 -13 455 198 -6-methyl-L prepared as described in Example 25) in trifluoroacetic acid (10 ml) and anisole (10 drops) was allowed to stand at room temperature overnight.

The reaction mixture was evaporated in vacuo and the residue was triturated. was partitioned between diethyl ether. The pale brown solid formed was filtered and recrystallized from acetone to give 3- (2-chloroethyl) -6-methyl-8-sulfamoyl- [3 3] -imidazole, 1-d] -1,2, 3,5- tetrazin-4-one (0.55 g), m.p. 199-ZOOOC (during decomposition). [ementlementar analysis C 29.1; H 3.02; N 28.8; Cl 12.1; S 10.6%; Calculated: C 28.72; H 3.10; N 28.71; Cl 12.11; S 10.9S%; I.R. 1760, 3310 cm'i7.

EXAMPLE 27 association AA A solution of 5-diazo-4-dimethylsulfamoyl-Z-methylimidazole (1.8 g; prepared as described in Example 15) in dry ethyl acetate (100 ml) was treated with 2-chloroethyl isocyanate (4 ml) and Among- The mixture was then treated with an additional quantity of 2-chloro- the mixture was allowed to stand for two days at room temperature. ethyl isocyanate (4 ml) and allowed to stand at room temperature for one hour additional time period of 6 days. The reaction mixture is evaporated was then evaporated in vacuo and the residue was decomposed with petroleum ether (b.p. eo-so ° c; 2 X zs m1). was dissolved in ethyl acetate and subjected to chromatography on medium high pressure silica gel eluting with ethyl acetate. Suitable fractions were combined, evaporated to dryness and decomposed. was partitioned with petroleum ether (b.p. so-so ° c) to give s- (z- chloroethyl) -8-dimethylsufamoyl-6-methyl- [š fi] -imidazo [ε, 1-d] -1,2,3,5- tetrazin-4-one (2.1 g), m.p. 137-138 ° C. Parliamentary analysis C 33.8; H 3.91; N 25.8; Cl 11.2; S 9.7%; calculated: C 35.7; H 4.09; X 26.20; Cl 11.05; S 10.02].

The remaining solid EXAMPLE 28 The association BB A solution of 5-diazo-2-methyl-4-methylsulfonylimidazole (0.4 μg prepared as described in Example 16) in dry ethyl acetate (30 ml) was treated with 2-chloroethyl isocyanate (2 ml) and allowed to stand at room temperature in the dark for 4 days. The mixture was evaporated then to dryness and the residue was decomposed with petroleum ether (b.p. 60-80 ° C; Z x ZS ml) to remove excess 10 15 20 ZS 30 35 455 198 M IN 2-chloroethyl isocyanate. The remaining residue was dissolved in ethyl acetate and chromatographed at medium pressure on silica gel eluting with ethyl acetate to give 3- (Z-Chloroethyl) -6-methyl-8-methylsulfonyl-ï 1,2,3,5-tetrazin-4-one (0.22 g), m.p. 149-150 ° C. [Elementarana- lys: C 33.0; H 3.35; N 23.8; Cl 12.7%; S 10.7%; calculated: c 32.94; H 3.46; N 24.01; c1 12.15; s 1o, 99æ; I.R. 1745 em'É1.

EXAMPLE 29 The association CC A suspension of 3-diazopyrazole-4- (§, §-dimethylcarboxamide) - hydrochloride (0.92 g; prepared as described in Reference Example 17) in dry dichloromethane (50 ml) was treated with 2-chloroethyl iso- cyanate (2.5 ml) and the stirred suspension was then treated with 1,8-diazobicyclofe, 4, Q] undec-7-ene (0.7 g). The solution obtained The mixture was stirred at room temperature in the dark overnight. Dichloro- the methane was evaporated off and the resulting rubber was decomposed with leumeter (b.p. 60-80 ° C). The insoluble residue was subjected chromatography at medium pressure eluting with ethyl acetate.

Appropriate fractions were combined, evaporated to dryness and the residue was recrystallized from ethyl acetate to give 3-12-chloroethyl) -8- (dimethylcarbamoyl) - [3 fi] - pyrazolo [3,1-d] -1,2,3,5- tetrazin-4-one (0.38 g) as colorless crystals, m.p. 116- 18 ° C (during decomposition). [Elemental analysis: C 39.7; H 3.96; N 30.9; Cl 13.1%; calculated: C 39.93; H 4.10; N 31.05; Cl 13.1%; 1.R. (rar-disk) = 1710, 1630 cm'1; NMR (1 scene-d6) = singier at 3.25 and 8.40 ppm, triplets at 4.25 ppm and 4.95 ppmj.

EXAMPLE 30 The association DD Rounded concentrated sulfuric acid (2.5 ml) was treated with 8-Carbamoyl-3- (2-chloroethyl) - [3§] -imidazo [S, 1-d] -1,2,3,5-tetra- zin-4-one (0.24 g; prepared as described in British Patents document No. 2104532). The mixture was cooled to 0 ° C and treated. des dropwise with concentrated nitric acid (d = 1.42; 1 ml).

The solution was kept at 4 ° C for 1 hour and then poured onto ice.

The precipitated solid was collected, washed with water and recrystallized from water-acetone to give 3- (2- chloroethyl) -8- (β-nitrocarbamoyl) - [3§7-imidazo [3,1-d7-1,2,3,5- tetrazin-4-one (0.28 g) as colorless crystals, m.p. 160- a .... 10 15 20 25 30 25 455 198 161 ° C (with decomposition). [Elemental analysis: C 28.6; H 1.89; c1 12.0; N 3s, 6%; calculated: c 29.23; H 2.10; c1 12.33; N s4.09%; 1 _I.R. (KB disk): 3200, l? 50, 1720 and l620 cm-; NMR (DMSO-d 6): triplets at 4.05 ppm (J = 6Hz) and 4.70 ppm (J = 6Hz), singly led at 9.05 ppm, wide singlet at 8.25 ppm; m / e 287/289 cM * l7.

EXAMPLE 31 The compounds EE, FF, GG, HH and II By proceeding in the same manner as described in the examples 1, 2, 4, 6 to 13, 1S to 25 and 27 to 29 and use of suitable diazo compounds as intermediates (produced by application or adaptation of methods described below reference examples) were prepared: 3-Methyl-5-methylsulfonyl- [η 5] -pyrazolo [5,1-di-1,1,3,5-tetra- zin-4-one in the form of a colorless solid, m.p. 182-184 ° C; 3- (2-chloroethyl) -8-methylsulfonyl-13§] -pyrazolo [3,1-d] -1,2,3,5- tetrazin-4-one in the form of a colorless solid, m.p. 166-171 ° C; 3- (2-chloroethyl) -6-methyl-8-methylminophinyl- [3§] -imidazo [B, 1-d] - 1,2,3,5-tetrazin-4-one as a yellow solid, m.p. 118- 120 ° C; 3- (2-chloroethyl) -8-ethylsulfonyl-6-methyl- [So] -imidazole, 1-d] - 1,2,3,5-tetrazin-4-one, m.p. 146-147 ° C; and 3- (2-chloroethyl) -6-methyl-8-propylsulfonyl- [η 5] -imidazo [B, 1- Q] -1,2,3,5-tetrazin-4-one in the form of a white crystalline solid substance, m.p. 85-86 ° C.

REFERENCE EXAMPLE 1 (i) An intimate mixture of 5-nitroimidazole-4-carboxylic acid acid (2.0 g) and phosphorus pentachloride (2.6T g) were stirred and stirred. heated on an oil bath at 120 ° C for 1 hour. It formed yellow the slurry was evaporated at 60 ° C / 0.1 mmHg for another 30 minutes formation of 1,6-dinitro-S§, 10§-diimidazo [L5 5,10-dione (1,9U g; as a yellow solid, mp 249-25l ° C (during decomposition). [l.R. (KBr disc): 1750 cm-1; m / e 278 ¿Windaus, Ber., 1923, âg, 684 and Gireva, Chem. Abs., Yoke, 1622e, using the same method describes the products as "S-nitroimidazole-4-carbonyl chloride fl j. (ii) A mixture of 1,6-dinitro-S fi, IOE-diimidazofl, 5-az 10 20 25 Ln O UI U1 40 ° C. 26 455 198 1 ', 5'-dipyrazine-5,10-dione (5.8 g), E-benzylaniline (15 g) and tetrahydrofuran (250 ml) was heated at reflux for 6 hours.

The tetrahydrofuran was evaporated in vacuo and the remaining rubber was partitioned between dilute hydrochloric acid (2N; 1 liter) and ethyl acetate. tat (1 liter). Insoluble §-benzylaniline hydrochloride was removed by filtration and the ethyl acetate layer was separated. The water phase was extracted twice more with ethyl acetate and the combined The organic phases were washed with dilute hydrochloric acid (ZN) and then with water, dried over magnesium sulphate and evaporated. was allowed to dry to give an orange gum. The rubber decomposed twice with boiling diethyl ether to give of a colorless solid, which was crystallized from isopropanol to form 5-nitroimidazole-4-§-benzyl-§-phenylcarboxamide (4.0 g) in the form of colorless flakes, m.p. 237 ~ 240 ° C. [Elemental- Analysis: C 62.3; H 4.28; N 17.3%; Calculated: C 63.35; H 4.38; N 17, ss%; 1.R. (xßr-skivay: 1665 cm'É7. (iii) A solution of 5-nitroimidazole-4-§-benzyl-§-phenyl- carboxamide (4.0 g) in dry ethanol (450 ml) was hydrogenated at 26 ° C and 3 atmospheres pressure using a Raney nickel catalyst lysator. When the hydrogen absorption was complete (after 4 hours and 50 minutes) the mixture was filtered, treated with concentrated hydrochloric acid (3.6 ml) and evaporated to dryness under Decomposition of the residue with diethyl ether gave 5-amino- imidazole-4-§-benzyl-§-phenylcarboxamide hydrochloride (3.82 g) in form of a pale yellow solid, m.p. 190-19390 (during decommissioning division) [NMR (in DMSO-d 6): singlets at 5.05, 7.1-7.2 and 8.4 ppm; I.R. [KBr disk]: 1640 cm_l; m / e 292 (M < + >)].

REFERENCE EXAMPLE 2 (i) A mixture of §-benzyl-¶- (4-methoxybenzyl) amine- [É1.9 g; Annals, (1931), QQQ. l8Q], 1,6-dinitro-S fi, 10 fl- di- imidazo [5,1-azl ', 5'-dipyrazine-5,10-dione (6.7 g; prepared as described in Reference Example 1)) and dry tetrahydro- The furan (200 ml) was heated at reflux for 18 hours. the hydrofuran was evaporated in vacuo and the residue oily the solid was partitioned between dilute hydrochloric acid (ZN, 500 ml) and ethyl acetate (500 ml). Insoluble §-benzyl-§- (4-methoxybenzyl) - amine hydrochloride was removed by filtration and ethyl acetate The aqueous phase was extracted with two Tetra- the layer is separated. with ethyl acetate and the combined organic phases wash 10 20 25 30 p [11 27. 455 198 taken with dilute hydrochloric acid (ZN), then with water and then with a saturated aqueous solution of sodium chloride, after which the was added to sodium sulfate and evaporated to dryness. The remaining "the rubber was subjected to column chromatography at medium height pressure eluting with ethyl acetate to give 5-nitro- imidazole-4-§-benzyl-1- (4-methoxybenzyl) carboxamide (2.9 g) in the form of a light brown solid, m.p. 167-170 ° C [after crystallization lysation from a mixture of petroleum ether (b.p. 60-80 ° C) and iso- propano1]. Basic analysis C 61.3; H 4.93; N 15.3%; calculated: c 62.29; H 4.95; N 1s, z9%; 1.12. (Ready disc: 3100-2800, 1640, 1510, 1450 and 1370 cm_1. NMR (in DMSO-die at 120 ° C): singlets at 3.76, 4.5, 4.6, 7.3 and 7.8 ppm, doublets centered at 6.85 and 7.2 ppm¿] (NMR spectrum at room temperature is complicated due to duplication of signals caused by obstructed rotation around the bond between the amide carbonyl group and the amide nitrogen atom). (ii) A solution of 5-nitroimidazole-4-§-benzyl-§- (4- methoxybenzyl) carboxamide (2.2 g) in dry ethanol (200 ml) was generated at room temperature and 3 atmospheric pressures during of a Raney nickel catalyst. When the hydrogen absorption was complete (after Z hours and 48 minutes) the mixture was filtered treated with hydrogen chloride gas and evaporated to dryness below 40 ° C. Decomposition with a mixture of isopropanol and diethyl ether gave 5-aminoimidazole-4-§-benzyl-§- (4-methoxybenzyl) - carboxamide hydrochloride (2.2 g) as a gummy solid substance, which decomposed above 70 ° C [1.R. (KBr disk): 3400- 2800, 1640 cm -1; NHR (in methanol-d4): singlets at 3.7, 4.4, 4.5, 7.2 and 8.3 ppm, doublets centered at 6.7 and 6.9 ppm (the signals were widened due to hindered rotation about the between the amide carbonyl group and the amide nitrogen atom).

REFERENCE EXAMPLE 3 (i) A mixture of 1,6-dinitro-SQ, 10-diimidazo [1,5-a: 1 ', 5'-d] pyrazine-5,10-dione (5.5 g: prepared as described in ference example 1), §- (4-methoxybenzyl) -aniline [14, S g; Zechmeister gt al, Ber., (1930), QÃB, 2885] and tetrahydrofuran (250 ml) hcttades at reflux for 12 hours. The tetrahydrofuran was evaporated then in vacuo and the remaining dark oil was partitioned between dilute hydrochloric acid (2M; 1000 ml) and ethyl acetate (1000 ml).

The organic layer was separated, washed with water, dried UI 10 20 25 455 198 was added over magnesium sulphate and evaporated to dryness. The car The solids were decomposed with diethyl ether to give 5-nitroimidazole-4-§- (4-methoxybenzyl) -§-phenylcarboxamide (3.18 g), in the form of a peach solid, m.p. 212-215 ° C (after recrystallization from isopropanol). Elemental analysis C 60.4; H 4.41; N 16.0%; Calculated: C 61.37; H 4.58; ä l5.9l%; NMR (i DMSO-d6): singlets at 3.7, 5.0 and 7.7 ppm, multiplet at 6.7-7.3 ppm; 1.R. çxßr-skiva) 1660 em'i]. (ii) A solution of S-nitroimidazole-4-§- (4-methoxybenzyl) - §-phenylcarboxamide (2.1 g) in dry ethanol (200 ml) was hydrogenated at 25 ° C and 3 atmospheres pressure using a Raney nickel catalyst. When the hydrogen absorption was complete (after 5 hours), the mixture was filtered and evaporated to dryness. The residue was triturated with diethyl ether to give 5-amino- imidazole-4-§- (4-methoxybenzyl) -§-phenylcarboxamide (1.9 g) in the form of a rubber. 7 ' the portion of this rubber was characterized as its picrate: 5-Aminoimidazole-4-§- (4-methoxybenzyl) -E-phenylcarboxamide (0.15 g) was dissolved in dry 1,2-dimethoxyethane (3 ml) and treated with a solution of picric acid (0.25 g) in 1,2-dimethoxyethane (5 ml). Form- the crystals were filtered off and washed with diethyl ether formation of 5-aminoimidazole-4-§- (4-methoxybenzyl) -§-phenylcarboxa- midpicrate (0.07 g) as a yellow solid, m.p. 207 ° C (during decomposition) Zïlementaranalvs; C 49.1; H 3.64; N 16.5%; C24H21N709: ZH2O. Required: C 49.1; H 4.29; N 16.6QZ}.

REFERENCE EXAMPLE 4 (i) A mixture of 1,6-dinitro-SH, IOH-diimidazo [1,5-a: 1 ', 5'-d] pyrazine-5,10-dione (8.08 g; prepared as described in Reference Example 1), N-methylaniline (12.44 g) and tetrahydrofuran (400 ml) was heated at reflux for 24 hours. Tetrahydrofura- the net was then evaporated in vacuo and the remaining dark solid treated with boiling diethyl ether. The remaining undissolved the solid was subjected to column chromatography at medium pressure eluting with a mixture of ethyl acetate and methanol (1: 1) vol / vol) to give 5-nitroimidazole-4-§-methyl-§-phenyl- carboxamide (4.68 g) as a white solid, m.p. 193 ° C.

Cylinder analysis C 52.5; H 3.95; N 22.2% calculated: C 53.66, H 4.09; N 22.1%; 1.R. 1660 cm'i7. 10 20 25 30 (J: UI 29 455 198 (ii) A solution of 5-nitroimidazole-4-§-methyl-§-phenylcar- boxamide (1.0 g) in dry ethanol (110 ml) was hydrogenated at 23 ° C and 3 atmospheres of pressure using a Raney key catalyst. When the hydrogen absorption was complete (after 1 hour me and 39 minutes) the mixture was filtered and treated with dry hydrogen chloride gas. The solution was then evaporated to dryness to form 5-aminoimidazole-4-§-methyl-§-phenylcarboxamide- hydrochloride (0.9 g) as an off-white solid, m.p. 100 ° C (during decomposition).

This compound was characterized as its pikrat: A solution of 5-aminoimidazole-4-β-methyl-E-phenylcarboxamide hydrochloride (0.25 g) in water (2 ml) was treated with a solution of picrin acid (0.25 g) in 1,2-dimethoxyethane (2 ml). The precipitate is filtered off. and washed with 1,2-dimethoxyethane to give 5-amino- imidazole-4-1-methyl-β-phenylcarboxamide picrate L0.12 g) in the form of a yellow solid, m.p. 237-238 ° C (with decomposition). tar analysis: C 45.3; H 3.26; N Z1, 8%; calculated: C 45.85; H 3.39; N z2, oz'z; 1.11. (tar-disc 1640 em'1_7}.

REFERENCE EXAMPLE 5 A stirred solution of sodium nitrite (1.0 g) in water (8 ml) cooled to 0 ° C and treated with a solution of 4-amino-Z- methylimidazole-5-carboxamide hydrochloride (2.0 g: prepared as described in West German Patent Specification No. 2358509) in water-vinegar acid (2N; 24 ml) while maintaining the temperature between -ZOC and 0 ° C. After the addition was complete, the yellow formed was filtered off solid and dried in vacuo over phosphorus pentoxide to give 5-diazo-2-methylimidazole-4-carboxamide (1,6g), m.p. 175 ° C (explodes).

REFERENCE EXAMPLE o (i) A stirred aqueous solution of dimethylamine (SM w / w; 35 ml) cooled in a cold water bath was treated with 5-nitroimidazole-4- phonyl chloride (4.5 g of moist material, freshly prepared from 3.53 g of 5-nitro imidazole-4-thiolammonium salt by the method of Fisher et al. Can. J. Chem., 32, 501) in portions. another 20 minutes and then evaporated in vacuo under The mixture The mixture was stirred during 40 ° C to reduce the volume by half. was then strongly acidified by treatment with concentrated hydrochloric acid, and the pale yellow solid formed was filtered off and 10 15 20 455 198 3 ” was recrystallized from dimethylformamide to give 5- nitroimidazole-4- (§, §-dimethylsulfonamide) (2.73 g) in the form of brown like plates, m.p. 282-28306 (subdivision) [Elementary Amalysis: C 27.3; H 3.65; N 25.4; S 14.2%; calculated: C 27.3; hrs 3.66; N 25.4; S 14.6%]. (ii) A solution of 5-nitroimidazole-4- (§, §-dimethylsulfonamide) (1.0 g) in dry ethanol (100 ml) was hydrogenated at 24 ° C and 3 atmospheric pressure using a Raney key catalyst.

The mixture was then filtered and immediately diluted with diethylene. ether (200 ml) and treated with dry hydrogen chloride gas until then that it was slightly sour. The mixture was then evaporated in vacuo at below 30 ° C. The remaining solid was dissolved in hot dry ethanol (20 ml), and the solution was treated with charcoal, was triturated, evaporated to 15 ml volume, treated with dry matter diethyl ether (60 ml) and allowed to crystallize. It formed solid the substance was filtered off to give 5-aminoimidazo1-4- (§, §-dí- methylsulfonamide) hydrochloride (0.8 g) in the form of a pinkish light brownish-yellow needles, m.p. 188-189 ° C (with decomposition). [Elementary- Analysis: C 26.1; H 4.80; N 23.6; Cl 15.9; S 13.9%; C5H14ON4O2S: HCl obtained C 26.5; H 4.85; N 24.7; Cl 15.6; S l4, l5% I. (iii) A stirred solution of sodium nitrite (0.3l g) in water (5 ml) cooled on an ice bath was treated dropwise with a solution of S- aminoimidazole-4- (fi-dimethylsulfonamide) hydrochloride (0.7 g) in dilute hydrochloric acid (2N; 5.1 ml). The solid formed, was filtered off and washed with ice-cold water to give s-aiazoimiaazo1-4- (yg-aimetyisuifonamia) (o, ss g), m.p. 1 ° C (during decomposition). (LR. Ziso, 2210 cnflj.

An additional portion (0.1 g) of slightly less pure product was obtained by extracting the aqueous phase at 0 ° C with ethyl acetate, drying of the extract over magnesium sulphate and evaporation in vacuum.

REFERENCE EXAMPLE T (i) A stirred aqueous solution of methylamine (Z5% w / w; 35 ml) cooled in a cold water bath was treated with 5-nitroimidazole- -sulfonyl chloride (4.1 g moist material, freshly prepared from 3.33 g 5-Nitroimidazole-4-thiolammonium salt according to the method of Fisher gt al., Gg¿ gi§¿) in portions. another 15 minutes and then evaporated in vacuo under The mixture was stirred during 10 20 ZS 35 31 455 198 40 ° C to reduce the volume by half. The mixture was made then strongly acidic by treatment with concentrated hydrochloric acid, and the resulting solid was filtered off and recrystallized from was extracted from water to give S-nitroimidazole-4- (N-methyl- sulfonamia) (2.0: g) 1 form of b1ekgu1a b1ad, m.p. 260-za3 ° c (during decomposition). Zblementar Analysis: C 23.1; H 2.87; N 27.4; S 15.4%; calculated: C 23.3; H 2.93; N 27.2; S 15.55%]. (ii) A solution of 5-nitroimidazole-4- (N-methylsulfonamide) (1.0 g) in dry ethanol (100 ml) was hydrogenated at 24 ° C and 3 atmospheres using a Raney key catalyst. Among- The mixture was then filtered and immediately diluted with diethyl ether (200 ml) and treated with dry hydrogen chloride gas until then that it was slightly sour. The mixture was then evaporated in vacuo at under SOOC. volume of ethanol, and the solution was treated with charcoal, filtered The remaining solid was dissolved at least and diluted with diethyl ether. The solid formed filtered to give 5-aminoimidazole-4- (N-methylsulfonyl) amide) hydrochloride (0.63 g), m.p. 178-180 ° C (during decomposition). [Elemental analysis: C 22.3; H 4.13; N 25.5; Cl 16.9%; C4H8N4O2S: HCl yield C 22.6; H 4.26; N 26.35; Cl 16.7å]. (iii) A stirred solution of sodium nitrite (0.285 g) in water (4 ml) cooled in an ice bath was treated dropwise with a solution of 5-aminoimidazole-4- (N-methylsulfonamide) hydrochloride (0.5S g) in dilute hydrochloric acid (2N; 2.8 ml). The solid formed was filtered off and washed with ice-cold water to give S-diazoimidazole-4- (N-methylsulfonamide) (0.36 g), m.p. 150 ° C (during decomposition). Elemental analysis C 25.2; H 2.47; N 37.0%; calculated; c zs, 7; H 2.69; N 37.4%; 1.R. 2210 cm -1], An additional portion (0.07 g) of the product was obtained by extraction of the aqueous phase at 0 ° C with ethyl acetate, drying of the extract over magnesium sulphate and evaporation in vacuo.

REFERENCE EXAMPLE 8 A solution of sodium nitrite (0.5 g) in water (5 ml) as maintained at 0 ° C was treated dropwise with a solution of 5-amino-4- methsulfonylimidazole hydrochloride 11.0 g; prepared as by Bennet: 53 31, J.A.c.s. lgígl, 2188-2191, (19s717 i The solution was stirred during written dilute hydrochloric acid (2N; 5 ml). 15 minutes and then extracted with ethyl acetate (5 x 20) ml). The combined extracts were dried over sodium sulfate and 10 15 20 25 35 "sz 455 198 evaporated in vacuo to leave a yellow oil, which crystallized stalled when allowed to give 5-diazo-4-methyl- sulfonyiimiaazoi (0.4 g), m.p. 128-1so ° c ¿ï.R. zizs cm "{].

REFERENCE EXAMPLE 9 (i) In a stirred solution of p-methoxybenzylamine (10 g) i water (30 ml) was treated with 5-nitroimidazole-4-sulfonyl chloride (6.8 g moist material, freshly prepared from 6.0 g 5-nitroimidazole-4- thiolammonium salt by the method of Fisher et al., gB.Eit.). É The mixture solidified rapidly to solid mass, after which it was treated. was added with isopropanol (20 ml) and decomposed and allowed to stand overnight. The resulting solid was filtered off, washed with ice-cold water and then suspended in water (150 ml) and was carefully treated with dilute hydrochloric acid (ZN) until then that the suspension barely reached pH2. It formed yellow the solid was filtered off and washed with a small amount of ice cold water to form 5-nitroimidazole-4- [§- (4-methoxybenzyl) sul- phonamide] (7.42 g), m.p. 269-270 ° C (during decomposition). (ii) A solution of 5-nitroimidazole-4- [fi- (4-methoxybenzyl) - sulfonamide7 (1.0 g) in dry ethanol (100 ml) was hydrogenated in 6 hours at 3 atmospheres using a Raney nickel lysator (50%). The catalyst was quickly filtered off with the aid of of diatomaceous earth, and the filtrate was immediately treated with The mixture was evaporated concentrated hydrochloric acid (20 ml). dryness and the residue formed was decomposed with diethylene ether. The solid was filtered off and washed with diethyl ether to give S-aminoimidazole-4- [Q-methoxybenzyl) sul- phonamiqy (o, zs ga, m.p. 154-1ss ° c. (iii) A solution of sodium nitrite (0.4 g) in water (5 ml) was treated dropwise with a solution of 5-aminoimidazo1-4- [E- (4-methoxybenzylsulfonamide (0.5 g) in dilute hydrochloric acid (2N; 10 ml) while maintaining the temperature at 0 ° C. The mixture stirred at 0 ° C for a further 15 minutes and the solid the substance was then filtered off, washed with water and dried over phosphorus pentoxide to give 5-diazoimidazole-4- [¶- (4- methoxybenzyl) sulfonamide (0.3 g), m.p. 144-146 ° C (during decomposition delníng) [ï.R. 2180 cm ~ ¥].

REFERENCE EXAMPLE 10 (i) A solution of piperidine (6.4 ml) in dry tetrahydro- UI 10 25 35 i * 455 198 furan (92 ml) was treated with 1,6-dinitrodiimidazo [1,5-a: 1 ', 5'-d7- pyrazine-5,10-dione (4.59 g; prepared as described in reference Example 1) and stirred at room temperature for 1 hour. Mixture- one was then evaporated and the residue was dissolved in dilute hydrochloric acid. acid (ZN; 92 ml). 200 ml) and the combined extracts were dried over magnesium sulfate. The solution was extracted with ethyl acetate (3x) barrels and evaporated. The residue was subjected to chromatography at medium pressure on silica gel eluting with a mixture of chloroform and methanol (9: 1 v / v). Appropriate fractions combined The mixture was evaporated and the residue was washed with diethyl ether followed by ethyl acetate to give 4-nitro-5-piperidinocarbon nylimidazole (Z, 72 g) as a yellow solid, m.p. 149-150 ° C.

Elemental Analysis C 48.2; H 5.33; N 2S, 1%; calculated: C 48.2; H 5.39; N 2s, o '~ J. (ii) A solution of 4-nitro-5-piperidinocarbonylimidazole (2, 3g; prepared as described above) in methanol (27 ml) and dimethylformamide (27 ml) was treated with platinum oxide (0.27 g), and the shaken mixture was hydrogenated at room temperature and atmospheric pressure. When hydrogen uptake was complete, the mixture was filtered and the filtrate was evaporated in vacuo. Re- The residue was dissolved in dilute hydrochloric acid (2N; 50 ml) and dissolved. The filtrate was filtered and the filtrate was evaporated in vacuo. It is- The residue was washed with acetone to give 4-amino- -5-piperidinocarbonylimidazole hydrochloride (2.1 g) as a pale green solid, m.p. 175-177 ° C sufficiently clean for use in the next step.

REFERENCE EXAMPLE ll (i) A stirred solution of 2-cyanoethylbenzene (5.0 g) and benzyl mercaptan (8.0 g) in dry dioxane (90 ml) was treated with hydrogen chloride gas to batch (5 hours) and allowed to stand at room temperature temperature for 5 days. The mixture was then treated with diethyl ether and the precipitate formed was filtered off and washed with ethyl ether to give S-benzyl-3-phenylpropionothioimidate hydrochloride (9.7 g) in form 158-160 ° C clean enough for use in the next step. of a colorless solid, m.p. (ii) A solution of α-amino-α-cyanoacetamide (3.3 g) in ethyl acetate nol (20 ml) was treated with crude S-benzyl-3-phenylpropionothioimi- dathydrochloride (9.7 g; prepared as described above) and the mixture was heated to reflux for 15 minutes. Mixture- 10 15 20 ZS 30 35 34 455 198 one was cooled and the solid formed was filtered off and recovered was stalled from methanol to give S-amino-2-phen® tY1- imidazole-4-carboxamide hydrochloride (2.3 g) as colorless crystals stables, m.p. 270-274 ° C. [Elemental analysis: C 53.8; H 5.55; N 2.1%; Cl 2 H 14 N 4 O: HCl obtained C 54.0; H 5.67; N 21.0å].

REFERENCE EXAMPLE 12 A solution of sodium nitrite (0.5 g) in water (15 ml) is kept at 0 ° C was treated dropwise with a solution of S-amino-2-benzene. syl-4-carbamoylimidazole (1.26 g; prepared as described in West German Patent Specification No. 2358509) in dilute hydrochloric acid (2N; 15 ml). The mixture was stirred at 0 ° C for a further period of 30 minutes, and the pale yellow solid formed was filtered off washed with water and dried in a desiccator over phosphor oxide to form 2-benzyl-5-diazoimidazole-4-carboxamide (0.8 g), m.p. 121-127 ° C (with decomposition) [1.R. 2180 cm_;].

REFERENCE EXAMPLE 13 (i) A solution of isobutyronitrile (6.9 g) and benzylmeric kaptan (20 ml) in dry dioxane (100 ml) was treated with dry hydrogen chloride gas for 3 hours at 0-10 ° C. The mixture was then allowed assume room temperature and the vessel was sealed and allowed to stand at room temperature for 14 days. The mixture was then poured into diethyl ether (1 liter), and the white precipitate formed was filtered off and washed with diethyl ether to give S-benzylisobutyl- thioimide hydrochloride (20.3 g), m.p. 165-166 ° C. [Elemental analysis: C 57.1; H 7.0; N 5.9; Cl 15.7; S 13.9%; Cl1J15NS: HCl obtained: C 57.5; 7.02; N 6.1; Cl 15.43; S 13.96%]. (ii) A solution of α-amino-α-cyanoacetamide (5.0 g) and S-benzylisobutylthioimidate hydrochloride (1.5 g; prepared as described above) in dry Z-ethoxyethanol (150 ml) was heated at reflux for 30 minutes. It formed the dark oil was decomposed with a mixture of chloroform and methanol (421 v / v; 100 ml) and the insoluble matter The filtrate was subjected to chromatography The solvent was evaporated. filtered and discarded. at medium pressure on silica gel eluting with a mixture of chloroform and methanol (421 v / v). Suitable fractions (identified by ninhydrin spray on a sample, which gave an intense yellowish brown color) were combined and evaporated to give of 5-amino-2-isopropylimidazole-4-carboxamide hydrochloride 10 15 20 25 30 35 35 455 198 (4.44 g) in the form of a gummy solid sufficiently pure for use in the next step. (iii) A solution of sodium nitrite (0.5 g) in water (5 ml) maintained at 0 ° C was treated dropwise with a solution of crude S-amino -Z-isopropylimidazole-4-carboxamide hydrochloride (1.1 g; prepared as described above) in an aqueous solution of acetic acid (2N; 20 ml). period of 5 minutes at 0 ° C and then extracted with ethyl acetate. tat (3 x 20 ml). sodium sulfate, concentrated in vacuo to a volume of 20 ml and was subjected to chromatography at medium pressure on silica gel The mixture was then stirred for an additional period of time. The combined extracts were dried over magnetic eluting with ethyl acetate. Appropriate fractions (identification with 2-naphthol spray on a sample, which gave a deep red color) combined and evaporated to dryness to give 5- dia: o-2-isopropylimidazole-4-carboxamide (0.4 g), m.p. 120 ° C (during decomposition). [l.R. 2170 cm_;].

REFERENCE EXAMPLE 14 (i) A cooled stirred solution of 2-methyl-5-nitroimidazole (127 g) in an aqueous solution of sodium hydroxide (S% w / v; 1500 ml) was treated with bromine (160 g) while maintaining the temperature hö11s at 15-zo ° c. 5.5 hours, and the solid which precipitated was dissolved by handling the mixture with an aqueous solution of sodium hydroxide (ZN). Traces of insoluble material were filtered off and the filtrate was acidified. was made to pH 1 by treatment with concentrated hydrochloric acid.

The mixture was stirred at room temperature in The white solid formed was filtered off, recrystallized from ethanol and dried in a desiccator over phosphorus pentoxide to formation of 4-bromo-2-methyl-5-nitroimidazole (151 g) as a white crystalline solid, m.p. 267-268 ° C. (ii) A stirred solution of 4-bromo-Z-methyl-5-nitroimidazole (20.6 g; prepared as described above) in an aqueous solution of ammonia (5N; 180 ml) was heated at 45 ° C and treated with a steady stream of hydrogen sulfide gas for 40 minutes. A yellow crystal lint solid formed slowly. The mixture was cooled in ice and the solid was filtered off, washed with ice water and dried. was desiccated over phosphorus pentoxide to give 4 ~ mer- capto-2-methyl-5-nitroimidazolammonium salt (14.6 g) which darkens without melting point below 300 ° C. [Blementar analysis C 27.2; H 4.41; N 31.6; S 18.2%; C 4 H 4 O 2 N 3 S: NH 4 gives C 27.27; H 4.58; N 10 15 20 '_11 Z 455 198 36 31.8; s 1s, 2ä7. (iii) An ice-cooled, vigorously stirred solution of 4-mercapto-2- methyl 5-nitroimidazole ammonium salt (3.5l g; prepared as written above) in dilute hydrochloric acid (1N; 120 ml) were treated Among- The mixture was stirred for a further period of 30 minutes with chlorine gas until a white solid has formed. at 0 ° C, after which the solid was filtered off, washed with water and dried in a desiccator over phosphorus pentoxide to 4-chlorosulfonyl-2-methyl-5-nitroimidazole (3.0 g); m.p. 160-162 ° C (with decomposition). Elemental analysis C 20.8; H 1.73; N 18.3; Cl 15.7; S 14.6%; Calculated: C 21.29; H 1.79; N 18.63; Cl 15.72; S l4,2lå7. (iv) A cooled solution of 4-methoxybenzylamine (5.48 g) in dry absolute ethanol (20 ml) was treated with 4-chlorosulfonyl-2- methyl 5-nitroimidazole (2.5 g; prepared as described above) and the mixture was stirred at room temperature for 3 hours. The yellow precipitates which were precipitated were filtered off, washed with ethanol and discarded as 4-methoxybenzylamine hydrochloride. They combined the filtrate and washings were evaporated to dryness and the obtained residue was suspended in water (50 ml), acidified to pH 1 by treatment with concentrated hydrochloric acid and was extracted with ethyl acetate (3 x 20 ml). The combined extracts The mixture was dried over magnesium sulfate and evaporated to dryness to give 4- (4-methoxybenzylsulfamoyl) -2-methyl-5-nitro- imidazole (2.77 g) as an off-white solid, m.p. 167- 170 ° C. [Elemental Analysis C 44.2; H 4.32; N 17.2; S 9.5%; Calculated: C 44.17; H 4.32; N 17.17; S 9.83%. (v) A solution of 4- (4-methoxybenzylsulfamoyl) -2-methyl- -5-nitroimidazole (4.5 g; prepared as described above) i dry ethanol (120 ml) was hydrogenated at 3 atmospheres pressure over a Raney nickel catalyst for 30 minutes. filtered and washed with dry ethanol (10 ml) and the combined The filtrate and washings were acidified to pH 1 by treatment with concentrated hydrochloric acid and evaporated to The catalyst Dryness. The resulting residue was triturated with diethyl ether to form 5-amino-4- (4-methoxybenzylsulfamoyl) -2-methyl- imidazohydrochloride (s, zs g); m.p. iss-1ss ° c. (vi) A solution of sodium nitrite (0.3 g) in water (5 ml) maintained at 0-5 ° C was treated dropwise with a solution of 5-amino- -4- (4-methoxybenzylsulfamoyl) -2-methylimidazole hydrochloride (1.0 g; 10 15 20 25 30 35 37 455 198 prepared as described above) in dilute hydrochloric acid (2N; 10 ml). The mixture was stirred for an additional period of time of 5 minutes at 0-SOC, and it formed orange solid The substance was filtered off, washed with water and dried in a desiccator. phosphorus pentoxide to give S-diazo-4- (4-methoxy- benzylsulfamoyl) -2-methylimidazole (0.75 g), m.p. 140 ° C (below decomposition) [I.R. 2200 cm_ {].

REFERENCE EXAMPLE 15 (i) An ethanolic solution of dimethylamine (33% w / v; 10 ml) was cooled and stirred and treated portionwise with 4- chlorosulfonyl-Z-methyl-5-nitroimidazole (2.25 g; prepared as described in Reference Example 14) and stirred at room temperature for an additional period of 45 minutes. The solution is was made to pH 1 by treatment with concentrated hydrochloric acid. acid, and the resulting white solid was filtered off and washed. was taken with cold water to give 4-dimethylsulfamoyl-2- methyl S-nitroimidazole (1.9 g), m.p. 240-Z41 ° C [Elemental analysis: C 30.5; H 4.24; N 23.8; S 13.8%: Calculated: C 30.77; H 4.3; N 23.92; S 13.69%; NMR (in DMS0-d6): singlets at 2.30 and ** 2.80 ppmj. (ii) A solution of 4-dimethylsulfamoyl-2-methyl-5-nitro- imidazole (12 g; prepared as described above) in dry ethanol (300 ml) was hydrogenated at 3.5 atmospheres pressure over a Raney nickel catalyst for 1 hour. The catalyst was filtered off and the filtrate was acidified to pH 1 by treatment with concentrated hydrochloric acid and evaporated to dryness. It formed the orange residue was triturated with diethyl ether to give 5-amino-4-dimethylsulfamoyl-2-methylimidazole (8.9 g, m.p. 215-217 ° C (during decomposition). (iii) A solution of sodium nitrite (1.0 g) in water Llš ml) maintained at 0 ° C was treated dropwise with a solution of 5-amino-4- dimethylsulfamoyl-2-methylimidazole (2.4 g) in dilute hydrogen chloride acid (ZN; 30 ml) and stirred for an additional period of time of 10 minutes at 0 ° C. The mixture was extracted with ethyl acetate (5 x 30 ml) and the combined extracts were dried over magnetic sodium sulfate, evaporated to dryness and decomposed with petroleum ether (Cf. §0-8000) to form S-diazo-4-dimethyl- sulfonyl-2-methylimidazole (1.8 g), m.p. ss-s1 ° c (during decomposition division) [1.R. 2180 cm'Ä]. 10 20 'J l 1: 1 38 455 198 REFERENCE EXAMPLE 16 (i) A solution of 4-mercapto-2-methyl-5-nitroimidazole ammonium salt (10, S g; prepared as described in reference Example 14) in methanolic sodium methoxide solution [prepared by Gently dissolve sodium (2.3 g) in dry methanol (250 mlL7) was treated with methyl iodide (10.7 g) and heated to reflux flow for 2 hours. The mixture was then evaporated to dryness and the residue was suspended in an aqueous solution of sodium oxide (2N; 100 ml). The suspension was filtered and the filtrate was acidified. was made to pH 1 by treatment with concentrated hydrochloric acid. acid to give 2-methyl-4-methylthio-5-nitroimidazole (9.0 g) in the form of a yellow solid, m.p. 236-237 ° C (during decomposition ning). Apple Elemental Analysis: C 34.7; H 4.04; N 24.3; S 18.5%; calculated: C 34.67: H 4.07; N 24.26; S l8.5l%]. (ii) A solution of 2-methyl-4-methylthio-5-nitroimidazole (3.46 g; prepared as described above) in glacial acetic acid (35 ml) was heated at 60 ° C and treated dropwise with an aqueous solution. hydrogen peroxide (30% w / v; 35 ml). The mixture is heated at 100 ° C for 15 minutes, cooled to room temperature and was traded with sufficient sodium sulfite for destruction of the excess hydrogen peroxide (detected by testing a sample with starch and potassium iodide). The mixture was subjected to then continuous liquid-liquid extraction with ethyl acetate in 20 hours.The extract was evaporated and the remaining white solid the substance was decomposed with petroleum ether (b.p. 60-80 ° C) and filtered off. was formed to give 2-methyl-4-methylsulfonyl-5-nitroimidazole (3.6 g), m.p. 222-2Z4 ° C Elemental analysis C 29.8; H 3.28; N 20.6; S 15.7%; Calculated: C 29.27; H 3.44; N 20.48; S l5.63å]. (iii) A solution of 2-methyl-4-methylsulfonyl-5-nitroimidamide zol (4.9 g; prepared as described above) in dry ethanol (400 ml) was hydrogenated at 3.5 atmospheres pressure over a Raney nickel catalyst for 30 minutes. The catalyst was filtered off and the filtrate was acidified to pH 1 by treatment with concentrated hydrochloric acid and evaporated to dryness, and the resulting the residue was triturated with diethyl ether containing traces of ethanol to give a purple solid, which filtered and washed with diethyl ether to give 5-amino- -2-methyl-4-methylsulfonylimidazole hydrochloride (4.1 g), m.p. if- around 300 ° C Elemental analysis C 27.3; H 4.51; N 19.9; Cl 17.9; S 13.72; Calculated: C 28.37; H 4.76; N 19.8; Cl 16.75; S l5, l5% 7. 10 15 25 30 b: J! 39 455 198 (iv) A solution of sodium nitrite (0.25 g) in water (5 ml) maintained at 0 ° C were treated dropwise with a solution of 5-amino- -2-methyl-4-methylsulfonylimidazole hydrochloride (0.53 g); forward set as described above). The mixture was stirred for one additional time period of 15 minutes at 0 ° C and extracted with ethyl acetate (S x 15 ml). The combined extracts were dried over magnesium sulphate and evaporated to dryness. The obtained the oil was decomposed with petroleum ether (b.p. 60-80 ° C) to give 5-diazo-2-methyl-4-methylsulfonylimidazole (0.4 g), m.p. 10 ° C (during decomposition) Äl.R. 2185 cm'i].

REFERENCE EXAMPLE 17 (i) A mixture of α-cyano-§, §-dimethylacetamide (8.2 g; prepared as described by Bowman et al., J. Chem. Soc., 1954, 1171), acetic anhydride (21 ml) and triethyl orthoformate (21 ml) was heated at 160-170 ° C in a flask equipped with a Mclintyre head for 90 minutes, during which time 26 ml of ethyl acetate lat was collected. The reaction mixture was concentrated in vacuo to form a dark oil, which was treated with ethanol (10 ml) and reconcentrated in vacuo. The residue is distilled was prepared at 160-170 ° C / 0.5 mmHg and then subjected to chromatography. graphite at medium pressure on silica gel eluting with ethyl acetate to form 2-cyano-3-ethoxy-§, §-dimethylpropehamide (5.3 g) in the form of an off-white, oily solid sufficient clean for use in the next step. _ (ii) A solution of crude 2-cyano-3-ethoxy-β, β-dimethylpropylene- amide (5.3 g; prepared as described above) in dry ethanol (50 ml) was treated dropwise with hydrazine hydrate (1.58 g). After completed addition, the mixture was heated at reflux for 6 hours and then evaporated to dryness. The remainder is chromatography was performed under medium pressure on silica gel eluting with with a mixture of chloroform and methanol (17: 3 v / v), and appropriate fractions were combined and evaporated to dryness. hot. The residue formed was dissolved in hot isopropanol (5 ml) and treated with concentrated hydrochloric acid (4 ml), and formed crystalline precipitate was collected to form 3-Aminopyrazole-4- (§, §-dimethylcarboxamide) hydrochloride (1.39 g) in the form of colorless crystals, m.p. 195 ° C. Lblementaranalysz C 37.8; H 5.82; N 29.0; Cl 18.3%; calculated: C 37.8; H 5.82; N 29.39; Cl l8.6 $; I.R. (KBr disc): 3500, 3400, 3000, 2200, 10 15 ZO 25 30 35 40 455 198 1655 em'1; NMR (1 nnso-α6); swimming at 3.0 and 8.1 ppm and broad singlet at 7.2 ppm1. (iii) A saturated solution of dry hydrogen chloride in dry methanol (70 ml) was treated with 3-aminopyrazole-4- (fi, β-dimethylcarboxylate). amide) hydrochloride (1.39 g; prepared as described above).

The stirred mixture was cooled to 0 ° C and treated with amyl nitrite (2, SS g) dropwise over 15 minutes while the temperature was maintained at 0 ° C. The resulting solution was allowed to stand 2-4 ° c 1 1 tmmme een häiidee then 1 a1eey1eter (800 m1).

The resulting solid was collected and washed with diethyl ether to form 3-diazopyrazole-4- (§, §-dimethylcarboxamide) - hydrochloride (0.9Z g) as colorless crystals, m.p. 150 ° C (explodes). [flementar analysis C 35.3; H 3.79; N 34.3%; C6H7- NH 4 Cl; HCl obtained: C 35.74; H 4.00; N 34.74%; I.R. (KBr disc): 3000-2100, zzso, 1630 cm'1_J.

The present invention includes within its scope pharmaceutical compositions which comprise as active ingredient at least one compound of the general formula shown in Fig. 1 as well as a pharmaceutical carrier or coating. In clinical In practice, the compounds of the general formula are administered as shown in Fig. 1 normally orally, rectally, parenterally for example intraperitoneally or intravenously, such as by infusion, or vaginally.

Methods for providing pharmaceutically active compounds are well known in the art and a suitable carrier can be determined by the doctor or pharmacist depending on such such as the desired effect, size, age, sex and the condition of the patient and the properties of the active compound.

The compositions may also contain such in the usual manner materials such as solid or liquid diluents, wetting agents agents, flavors, colorants and the like.

Solid compositions for oral administration include compressed tablets, pills, dispersible powders and granules. In such solid compositions, one or more of them is active the compounds mixed with at least one inert diluent, such as calcium carbonate, potato starch, alginic acid or lactose. Composi- the ions may also, as in normal practice, include additional substances in addition to inert diluents, such as lubricants, such as magnesium stearate. Liquid compositions for oral administration includes pharmaceutically acceptable emulsions, solvents 10 15 20 25 30 35 41 455 198 suspensions, syrups and elixirs containing inert particles commonly used in the art, such as water and tande paraffin. In addition to inert diluents, such .positions also include additives, such as wetting and pending agents, for example polyvinylpyrrolidone, and sweetening, flavorings, perfumes and preservatives. The compositions according to the invention for oral administration also includes of absorbable material, such as gelatin, containing a or several of the active substances with or without the addition of diluents or excipients.

Solid compositions for vaginal administration include pessaries formulated in a manner known per se and containing one or more of the active compounds.

Solid compositions for rectal administration include suppositories formulated in a manner known per se and included one or more of the active compounds.

Formulations according to the invention for parenteral administration include sterile anhydrous or anhydrous solutions, pensions or emulsions. Examples of anhydrous solvents or suspending media are polyethylene glycol, dimethyl sulfoxide, vegetable oils, such as olive oil, and injectable organics esters such as ethyl oleate. These compositions may also include adjuvants, such as preservatives, wetting agents, emulsifying and dispersing agents average. They can be sterilized, for example, by filtration through a bacterial filter, by incorporating sterilizing agents in the compositions or by ordering. They can too are prepared in the form of sterile solid compositions which can dissolved in sterile water or other sterile injectable material medium immediately before use.

The percentage of active ingredient in the composition according to the invention can be varied, where necessary that it should constitute such a proportion, that an appropriate dose for desired therapeutic effect must be achieved. Obviously, several can unit dosage forms are administered at approximately the same time. I all- In general, the preparations should normally contain at least 0,025 cents of the active substance when administered by injection including administration by infusion; for oral administration tion, the preparation normally contains at least 0.1% by weight of active substance. The dose used depends on the desired therapeutic effect, method of administration and duration of treatment. 10 15 20 25 30 35 455 198 “Z The tetrazine derivatives of the general formula I are useful in the treatment of malignant neoplasms, for example carcinoma, melanoma, sarcoma, lymphoma and leukemia, at doses which are generally is between 0.1 and 200, preferably between 1 and 20 mg / kg body weight per day.

The following compositional examples illustrate pharmaceuticals compositions of the present invention.

COMPOSITION EXAMPLE 1 A solution suitable for parenteral administration is prepared. was made up of the following ingredients: 8- (§-benzyl-§-phenylcarbamoyl) -3-methyl- [ïfi] -imidazole, 1-d] -1,2,3, 1.0 g 10 ml 5-tetrazin-4-one dimethyl sulfoxide by dissolving 8- (fl-benzyl-§-phenylcarba- moyl) -3-methyl- [Bg] -imidazo [5,1-d7-1,2,3,5-tetrazin-4-one] in di- methyl sulfoxide. The resulting solution was partitioned between technical conditions in ampoules in an amount of 1.1 ml per ampoule.

The ampoules were sealed to form 10 ampoules each containing containing 100 mg of 8- (E-benzyl-Q-phenylcarbamoyl) -3-methyl- [3§] - imidazo [S, 1-d] -1,2,3,5-tetrazin-4-one.

Similar ampoules containing solutions suitable for teral administration can be prepared by proceeding on the same way but replace 8- (¶-benzyl-§-phenylcarbamoyl-3-methyl- [3§] -imida- zo [B, 1-d] -1,2,3, S-tetrazin-4-one with another compound having the general formula shown in Fig. 1.

COMPOSITION EXAMPLE 2 A solution suitable for parenteral administration was prepared of the following ingredients: 3- (Z-chloroethyl) -8- (E-methylsulfamoyl) -3β-imidazo [3,1-d] -1,2,3,5- tetrazin-4-one 1.0 g dimethyl sulfoxide 10 ml arachis oil 90 ml by dissolving 3- (2-chloroethyl) -8- (§-methyl- sulfamoyl) - [Kg] -imidazo [5,1-d] -1,2,3,5-tetrasin- 4-one in the dimethyl sulfoxide and addition of the arachis oil.

The resulting solution was partitioned under aseptic conditions into ampoules in an amount of 10 ml per ampoule. The ampoules were closed to form 10 ampoules each containing 100 mg of (3- (Z- 10 15 455 198 43 chloroethyl) -8- (§-methylsulfamoyl) - [Bg] -imidazo [ε, 1-d] -1,2,3,5-tetra- zin-4-one.

Similar ampoules containing solutions of suitable for parenteral administration can be prepared by proceeding with the same way but replace 3- (Z-chloroethyl) -8- (§-methylsulfamoyl) -L3 fi] - imidazo [B, 1-d] -1,2,3,5-tetrazin-4-one against another compound with the general formula shown in Fig. 1.

COMPOSITION EXAMPLE 3 Capsules suitable for oral administration were prepared by placement of 3- (2-chloroethyl) -8- (§-methylsulfamoyl) - [3§7-imidazo- [3,1-d] -1,2,3,5-tetrazin-4-one in size 2 gelatin casings in an amount of 10 ml per capsule.

Similar capsules can be prepared using a another compound of the general formula shown in FIG. In or any other capsule housing of suitable size. 455 198 “4 RZ. v Rll A2 \ When? ) § (N§ \\ l / N N N T A \ \\ / N N Y al Y \ R10 Z 0 FIG- I FIG- II Rlu f / Aklíe z? \ N§ 'f ää šl / N nu N a »\ Rl 2 Zl FIG. III FIG.V MN§N å N \ IQ \. A \ Mif N \ | / N \ \\ 1 NY Rl A / Nïí \ Rl Z FIG. VI FIG. VII

Claims (33)

- ~ -; -.-_,; _ | 9 .., ._-. 45 455 198 PATENT CLAIMS Tetrazine derivatives of the general formula: wherein R 1 represents a cycloalkyl group having 3 to 8 carbon atoms, a straight or branched chain alkyl, alkenyl radical. or alkynyl group containing up to 6 carbon atoms, each such alkyl, alkenyl or alkynyl group being unsubstituted or substituted with from one to three substituents selected from halogen atoms, straight or branched chain alkoxy, alkylthio, alkylsulfinyl and alkylsulfonyl groups , which contain up to 4 carbon atoms, and phenyl groups, which are optionally substituted by halogen atoms, alkyl or alkoxy groups containing up to 4 carbon atoms or a nitro group, A represents a nitrogen atom or a group -CR 3 =, wherein R represents a hydrogen atom or a substituent R 4, wherein R 4 represents a halogen atom or a straight or branched chain alkyl or alkenyl group, which contains up to 6 carbon atoms and which may bear up to 3 substituents selected from halogen atoms, phenyl group which are optionally substituted by halogen atoms, alkyl or alkoxy groups containing up to 4 carbon atoms or a nitro group, straight or branched chain alkoxy, alkylthio and alkylsulfonyl groups containing up to 3 carbon atoms, or R4 represents a cycloalkyl group with 3-8 carbon atoms, cyano, hydroxy, nitro or phenoxy group, which is optionally substituted by halogen atoms, alkyl or alkoxy groups containing up to 4 carbon atoms or a nitro group, or a group of the formula -COR5 (wherein R5 represents an alkyl or alkoxy group having up to 4 carbon atoms or a hydroxy group or a phenyl group, which is optionally substituted by halogen atoms, alkyl or alkoxy groups containing up to 4 carbon atoms or a nitro group) or an alkanoylamino group containing up to 6 carbon atoms, or R 4 represents a group of the formula -S (O) n R 6, -SO 2 NR 7 R 8 -C 2 2 NR 7 R 8 (wherein n represents 0, 1 or 2, R 6 represents or a radical). is a branched chain alkyl or alkenyl group containing up to 4 carbon atoms, which may bear a phenyl substituent which is optionally substituted by halogen atoms, alkyl or alkoxy groups containing up to 4 carbon atoms or a nitro group, a cycloalkyl group having 3-8 carbon atoms or a phenyl group , which is optionally substituted by halogen atoms, alkyl or alkoxy groups containing up to 4 carbon atoms or a nitro group, R7 and R8, which may be the same or different, each representing a hydrogen atom or a straight or branched chain alkyl or alkenyl group, which contains up to to 4 carbon atoms and which may bear a phenyl substituent, which is optionally substituted by halogen atoms, alkyl or alkoxy groups containing up to 4 carbon atoms or a nitro group, or a cycloalkyl group having 3-8 carbon atoms or a phenyl group, which optionally is substituted by halogen atoms, alkyl or alkoxy groups containing up to 4 carbon atoms or a nitrogru pp, or the group -NR 7 R 8 represents a piperidino group, which is optionally substituted by one or two methyl groups, or a morpholino, pyrrolidin-1-yl, perhydroazepin-1-yl, piperazin-1-yl , 4-methylpiperazin-1-yl or 1,4-thiazin-1-yl group, and Z 2 represents an oxygen or sulfur atom), A 2 represents a nitrogen atom or when A 1 represents a nitrogen atom A 2 represents a nitrogen atom or a group -CR 3 =, wherein R 3 is as defined above, Z 1 represents an oxygen or sulfur atom and R 2 represents a group of the formula -S (O) n R 6, -so 2 NR 7 R 8, -csNR 7 R 8, -coNR 7 R 9 or -C R 5 and Z 2 are as defined above and the group -NR 7 R 9 represents a heterocyclic group, or R 7 is as defined above and R 9 represents a straight or branched chain alkyl or alkenyl group containing up to 4 carbon atoms, which bears a phenyl substituent, which optionally is substituted by halogen atoms, alkyl or alkoxy groups containing up to 4 carbon atoms or a nitro group, or a phenyl group, which is optionally substituted by halogen atoms, alkyl or alkoxy groups containing up to 4 carbon atoms or a nitro group, or when A1 represents a hydrogen atom or a group -CR4 =, wherein R4 has the meaning given above and Z 1 and A 2 have the meaning given above, or when A 1 represents a group -CH = and Z 1 represents a sulfur atom and A 2 has the above 41 in 455 198 meaning, R 2 represents a group of the formula -S (O) n R 6, -so 2 Na 7 R 8, cz 2 NR 7 R 8 or czznnuoz, wherein n, RÖ, 1: 7, 118 and zz have the meaning given above? and when R 2 and / or R 5 represent a sulfamoyl or monosubstituted sulfamoyl group and / or R 5 represents a carboxy group, salts thereof. ' A tetrazine derivative according to claim 1, wherein R 1 has the meaning given in claim 1, R 2 represents a carbamoyl group optionally substituted on the nitrogen atom with one or two groups selected from straight and branched chain alkyl and alkenyl groups containing up to 4 carbon atoms and cycloalkyl groups containing 3 to 8 carbon atoms, A1 represents a group -CR =, wherein R4 represents a straight or branched chain alkyl or alkenyl group containing up to 6 carbon atoms, which may bear up to 3 substituents selected from halogen atoms and phenyl groups , which are optionally substituted with halogen atoms, alkyl or alkoxy groups containing up to 4 carbon atoms or a nitro group, or R4 represents a cycloalkyl group containing 3 to 8 carbon atoms, AZ represents a nitrogen atom and Z1 represents an oxygen atom. A tetrazine derivative according to claim 1, wherein R 1 has the meaning given in claim 1, R 2 represents a group of the formula -s (o) n R 6 or -so 2 NR 7 R 8 R 6 represents a straight or branched chain alkyl or alkenyl group, which contains up to 4 which may bear a phenyl substituent optionally substituted by halogen atoms, alkyl or alkoxy groups containing up to 4 carbon atoms or a nitro group, a cycloalkyl group containing 3 to 8 carbon atoms or a phenyl group which is optionally substituted by halogen atoms , alkyl or alkoxy groups containing up to 4 carbon atoms or a nitro group, R 7 and R 5, which may be the same or different, each representing a hydrogen atom or a straight or branched chain alkyl or alkenyl group, which contains up to 4 carbon atoms and which, wherein n represents 0, 1 or 2, may bear a phenyl substituent, which is optionally substituted by halogen atoms, alkyl or alkoxy groups containing up to t 4 carbon atoms or a nitro group, or a cycloalkyl group containing 3 to 8 carbon atoms or a phenyl group, which is optionally substituted by halogen atoms, alkyl or alkoxy groups containing up to 4 carbon atoms or a nitro group, Al represents the group = CH- , A2 represents a nitrogen atom and Z represents an oxygen atom. A tetrazine derivative according to claim 1, wherein R 1 has the meaning given in claim 1, R 2 represents a group of the formula -s (o) n R 6, -so 2 NR 7 R 8 or -cz 2 NR 7 R 8 (wherein 3 represents o, 1 or 2, R represents a straight or branched chain alkyl or alkenyl group, which contains up to 4 carbon atoms and which may bear a phenyl substituent, which is optionally substituted by halogen atoms, alkyl or alkoxy groups containing up to 4 carbon atoms or a nitro group, a cycloalkyl group containing 3 to 8 carbon atoms or a phenyl group, which is optionally substituted by halogen atoms, alkyl or alkoxy groups containing up to 4 carbon atoms or a nitro group, R 7 and R 8, which may be the same or different, each representing a hydrogen atom or a straight or branched chain alkyl or alkenyl group, which contains up to 4 carbon atoms and which may bear a phenyl substituent, which is optionally substituted by halogen atoms, alkyl or alkoxy groups containing u pp to 4 carbon atoms or a nitro group, or a cycloalkyl group containing 3 to 8 carbon atoms or a phenyl group, which is optionally substituted by halogen atoms, alkyl or alkoxy groups containing up to 4 carbon atoms or a nitro group, A1 represents a nitrogen atom, A2 represents centers a group -CR 3 =, wherein R 3 represents a hydrogen atom or a substituent R as defined in claim 1, and Z 1 represents an oxygen or sulfur atom. A tetrazine derivative according to claim 1, wherein R 1 has the meaning given in claim 1, R 2 represents a carbamoyl group, which on the nitrogen atom bears (i) two groups selected from phenyl and phenylalkyl groups, which are optionally substituted by halogen atoms, alkyl or alkoxy groups containing up to 4 carbon atoms or a nitro group; or (ii) a phenyl or phenylalkyl group, which is optionally substituted by halogen atoms, alkyl or alkoxy groups containing up to 4 carbon atoms or a nitro group; or (iii) a phenyl or phenylalkyl group optionally substituted with halogen atoms, alkyl or alkoxy groups containing up to 4 carbon atoms or a nitro group, and a straight or branched chain alkyl group containing from 1 to 4 carbon atoms, A1 represents the group 49 455 198 = CH-, A2 represents a nitrogen atom and Z1 represents an oxygen atom. A tetrazine derivative according to any one of claims 1 to 5, in which the intended cycloalkyl group is cyclohexyl. The tetrazine derivative according to claim 1, wherein the intended heterocyclic group is an S-, 6- or 7-membered heterocyclic group, which may optionally bear an additional heteroatom selected from nitrogen, oxygen and sulfur, and which may bear one or two straight or branched chain alkyl substituents each containing up to 4 carbon atoms. hrs Tetrazine derivatives according to claim 1, which have one or more of the following characteristics: (i) R 1 represents a methyl or 2-haloethyl group; (ii) R 2 represents a group of the formula -SOR, -SOZR, -SOZNR R, -CONR R or -CONHNO 2, wherein R, R and R 5 are as defined in claim 1; (iii) one of A 1 and A 2 represents a nitrogen atom and the other represents a group -CR 3 =, wherein R 3 has the meaning given in claim 1; (iv) R 3 represents a substituent R 4, wherein R 4 represents an alkyl group containing up to 6 carbon atoms; (v) A2 represents a nitrogen atom; (vi) Z1 represents an oxygen atom; and / or (vii) Z represents an oxygen atom. A tetrazine derivative according to claim 8, wherein R 1 represents the 2-chloroethyl group. The tetrazine derivative according to claim 8, wherein R 2 represents a group -soR 6, -so, R 0, -so, NR 7 R 8, -coNR 7 R 8 or -coNHNoP were: R represents an enyalkyl group containing up to 4 carbon atoms, R 7 represents a hydrogen atom or an alkyl group containing up to 4 carbon atoms and R 8 represents a hydrogen atom, an alkyl group containing up to 4 carbon atoms or a benzyl group optionally substituted with an alkoxy group. ll. Tetrazine derivatives according to claim 8 or 10, in which the alkyl group is methyl. The tetrazine derivative according to claim 1, which is 8-carbamoyl--3- (2-chloroethyl) -6-methyl-α-imidiazophosphate, 1-d] -1,2,3,5-tetrazin-4-one. 455 198 S0 The tetrazine derivative according to claim 1, which is 3- (2-chloroethyl] -6-methyl-8-sulfamoyl- [E1E-imidazo [3,1-Q7-1,2,3,5-tetrazine-4] -on. A tetrazine derivative according to claim 1, which is 3- (2-chloroethyl) -8-dimethylsulfamoyl-6-methyl- [3§] -imidazo [ε, 1-Q] -1,2,3,5- tetrazin-4-one. The tetrazine derivative according to claim 1, which is 3- (2-chloroethyl) -8- (dimethylcarbamoyl) - [η 5 -pyrazolo [ε, 1-d] -1,2,3,5-tetrazine-4- on. The tetrazine derivative according to claim 1, which is 3- (2-chloro-ethyl) -8- (§, §-dimethylsulfamoyl) - [Bg] -imidazo [3,10] -1,2,3, S--tetrazine -4-on. The tetrazine derivative according to claim 1, which is 3- (2-chloroethyl) -8- (β-methylsulfamoyl) -β-imidazo [,,10] -1,2,3,5-tetrazine-4 -on. _ The tetrazine derivative according to claim 1, which is 3- (2-chloro-ethyl] -8-sulfamoyl- [3§] -imidazo [ε] -1- @ 7-1,2,3, S-tetrazin-4-one. A tetrazine derivative according to claim 1, which is 3- (Z-chloroethyl) -6-methyl-8-methylsulfonyl- [3§] -imidazo [S, 1-q] -1, Z, 3,5- tetrazin-4-one. The tetrazine derivative according to claim 1, which is 8- (§-benzylcarbamoyl) -3- (2-chloroethyl) - [š fi] - imidazo [3,1-Q] -1,2,3,5-tetrazine. -4-on. The tetrazine derivative according to claim 1, which is 3- (2-chloroethyl) -8-methylsulfonyl- [α] -imidazo- [ε, 1-4] -1,2,3,5-tetrazine-4- on. The tetrazine derivative according to claim 1, which is 3-methyl-8-methylsulfonyl- [3§] -imidazo- [ε, 1-Q] -1,2,3,5-tetrazin-4-one. The tetrazine derivative according to claim 1, which is 3- (2-chloroethyl) -8- [K- (4-methoxybenzyl) -sulfamoyl- [3§] -imidazo [3,1-Q7- -1,2, 3, S-tetrazin-4-one. The tetrazine derivative according to claim 1, which is 8-carbamoyl--3- (2-chloroethyl) - [η 5] -pyrazolo- [S, 1-d] -1,2,3,5-tetrazin-4-one. The tetrazine derivative according to claim 1, which is 3- (Z-chloroethyl) -8-piperidinecarbonyl- [3§] -imidazo [3,1-Q] -1,2,3,5-tetrazine-4 on. p The tetrazine derivative according to claim 1, which is 6-butyl-8-carbamoyl-3- (2-chloroethyl) - [η 5] -imidazo [ε, ld] -1,2,3,2-tetrazine-4- on. 'li' a .. 51 455 198 The tetrazine derivative according to claim 1, which is 8-carbamoyl-3- (2-chloroethyl) -6-propyl-β] -imidazo [S, 1-d] -1,2,3,3-tetrazine-4 -on. The tetrazine derivative according to claim 1, which is 8-carbamoyl-3 <(2-chloroethyl) -6-ethyl- [§§] -imidazo [3,1-d] -1,2,3,5-tetrazine -4-on. The tetrazine derivative according to claim 1, which is 3- (2-chloroethyl) -8- (E-nitrocarbamoyl) - [η 5 -imidazo [ε, ld] -1,2,3,5-tetrazine-4- on. The tetrazine derivative according to claim 1, which is 8- (§- -benzyl-§-phenylcarbamoyl) -3-methyl-α, fi] -imidazo [3,1-q? -1,2,3,5- -tetrazine-4 -one, 8- [fi-benzyl-β- (4-methoxybenzyl) -carbamoyl] -3- - (2-chloroethyl) - [QQY-imidazo [ε, 1,47-1,2,3,3-tetrazine -4-one, 3- (2-chloroethyl) -8-β- (4-methoxybenzyl) -§-phenylcarbamoyl] - [3§7-imidazo [ε, 1-Q] -1,2,3,5 ~ tetrazin-4-one, 3- (2-chloroethyl) -8- (§- -phenylcarbamoyl) - [Sa] -imidazo [3,1-d] -1,2,3,5-tetrazin-4-one, 8- (E-Benzyl-E-phenylcarbamoyl) -3- (2-chloroethyl) - [3§7-imidazo [3,1--Q] -1,2,3,5-tetrazin-4-one, 3 - (2-chloroethyl) -8- (§-methyl-§-phenyl-carbamoyl) - [Eg] -imidazo [3,1-d] -1,2,3,5-tetrazin-4-one, 8-carbamo moyl-3-methyl-ï [3,1-§7-1,1,3,3,5-tetrazin-4-one, 8-carbamoyl-3- (2-chloroethyl) -6-phenethyl] - [α] -phimidazo [S, 1-d ] -1,2,3,5-tetrazin-4-one, 6-benzyl-8--carbamoyl-3- (2-chloroethyl) - [η 5 -imidazo [3,1-d] -1,2,3 , S-tetrazin-4-one, 8-carbamoyl-3- (2-chloroethyl) -6-isopropyl-η 5] -imidazo [3,1--Q] -1,2,3,5-tetrazin-4 -on, 3- (2-kl orethyl) -8- (4-methoxybenzyl) -sulfamoyl-6-methyl- [η 5 -imidazo [S, 1-d] -1,2,3,5-tetrazin-4-one, 3-methyl-8-methylsulfonyl - [Bg] -pyrazolo [ε, 1-d] -1,2,3,3-tetrazin-4-one, 3- (2-chloroethyl) -8-methylsulfonyl- [3§] -pyrazolo [3, 1-d] -1-Z, 3,5-tetrazin-4-one, 3- (2-chloroethyl) -6-methyl-8-methylsulfinyl- - [3 §7-imidazo [É, ld] -1 , 2,3,5-tetrazin-4-one, 3- (2-chloroethyl) -8-ethylsulfonyl-6-methyl- [3§] -imidazo [E, ld] -1,2,3,5- tetrazin-4-one and 3- (2-chloroethyl) -6-methyl-8-propylsulfonyl- [3fi] -imidazo- [1,1d] -1,2,3,5-tetrazin-4-one. A process for the preparation of tetrazine derivatives having the general formula given in claim 1, which process comprises: (A) when R 2 has a meaning other than a sulfamoyl, mono (phenyl optionally substituted by halogen atoms, alkyl or alkoxy). 52 groups containing up to 4 carbon atoms or a nitro group) - carbamoyl or mono (phenyl optionally substituted by halogen atoms, alkyl or alkoxy groups containing up to 4 carbon atoms or a nitro group) thiocarbamoyl, nitrocarbamamo or nitrothiocarbamoyl group, reaction of a compound with the general formula: 1 »Åse Ne nlz Näe (wherein A1 and A2 have the meaning given in claim 1 and R1z represents a group within the definition of R2 in claim 1 other than a sulfamoyl, mono (phenyl optionally substituted by halogen). atoms, alkyl or alkoxy groups containing up to 4 carbon atoms or a nitro group) carbamoyl or mono (phenyl optionally substituted by halogen atoms, alkyl or alkoxy groups containing up to 4 carbon atoms or a nitro group) thiocarbamoyl, nitrocarbamoyl or nitrothiocarbamoyl group, having a compound of the general formula: Rluczl wherein R1 and Z1 have the meaning given in claim 1; (B) when R 2 represents a sulfamoyl, monosubstituted sulfamoyl, carbamoyl, monosubstituted carbamoyl, thiocarbamoyl or monosubstituted thiocarbamoyl group, and - R 1, A 1, A 2 and Z 1 have the meaning given in claim 1, debenzylation of a compound with the general formula: Rl7 Hr. reach; NN is R 2 (wherein R 17 represents a group -SO 2 NR 7 R 13 or -C 2 ZNR 7 R 13, wherein R 13 represents a benzyl group, which is optionally substituted by halogen atoms, alkyl or alkoxy groups 455 198 S3 containing up to 4 carbon atoms or a nitro group, and Z 2 and R 7 have the meaning given in claim 1] by applying or adapting per se known processes for the exchange of optionally substituted benzyl groups to hydrogen atoms; (C) when R 1, A 1, A 2 and Z 1 have the meaning given in claim 1 and R 2 represents a group of the formula - C 2 NHNO 2, wherein Z 2 has the meaning given in claim 1; nitration of a corresponding compound of the general formula: XN 2 + N A 2 I V / N R 1 Z 1 (wherein Z 2, R 1, A 1, A 2 and Z 1 have the meaning given in claim 1 ) for the conversion of the group -CZZNHZ to -CZZNHNOZ; (D) when R1, A1, A2 and RZ have the meaning given in claim 1 and Z represents a sulfur atom, reaction of a compound of the general formula: R15 Mmm A '§ 1 N Af * \ ïr / N \\ $ R1 O (wherein R1, Al and R2 have in kr of R 1 and R 1 represents a group of the formula -S (O) n R 6, -SO 2 NR 7 R 8, JCZZNR 7 R 8 or -C 2 ZNHNO 2, R 6, R 7, R 8, n and Z 2 have the meaning given in claim 1) with phosphorus pentasulfide for conversion of _ \\ ff C - unit II _ \ / 0 to C; or š (E) when a1, A1, A represents a group of the formula -CSNR7R8, wherein R7 and R8 2 and Z1 have the meaning given in claim 1 and R2 455 198 54 has the meaning given in claim 1, reacting a corresponding compound with the general formula: wherein N1, A1, A2, z1, R7 with phosphorus pentasulfide for the conversion of the group -CONR7R8 to -CSNR78; and when the obtained tetrazine product is a compound 3 and R8 has in claim 1) having the general formula given in claim 1, wherein R 2 and / or R represents a sulfamoyl or monosubstituted sulfamoyl group and / or R 5 represents a carboxy group, optionally converting the tetrazine product by a process known per se to a salt, preferably an alkali metal salt. Pharmaceutical compositions which comprise as active ingredient at least one tetrazine derivative according to any one of claims 1 to 30 in association with a pharmaceutically acceptable carrier or coating. A tetrazine derivative having the general formula of claim 1, wherein R 1, R 2, A 1, A 2 have meaning, for use in the treatment of malignant neoplasms, and Z 1 has as claimed in claim 1 such as carcinoma, melanoma, sarcoma, lymphoma and leukemia.